Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Brain–body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis

Nature Reviews Neurology volume 20, pages 475–494 (2024)Cite this article

Subjects

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons, leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3–5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals. However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease.

Key points

  • The molecular mechanisms that underlie sex differences in amyotrophic lateral sclerosis (ALS), in particular the higher prevalence and earlier onset in male over female individuals, are poorly understood.

  • The disease mechanisms are modulated by age, genetics and environmental factors that interact to produce a wide range of ALS phenotypes with differences in symptom presentation and disease onset and duration.

  • Interactions between the nervous systems and peripheral organs and systems that are strikingly different between sexes in terms of molecular signature and physiology are key to our understanding of sexual dimorphism in ALS.

  • Harnessing brain–body interactions could allow the identification of biomarkers and offer new avenues for the treatment of ALS.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sex differences in amyotrophic lateral sclerosis (ALS) symptoms and presentation.
Fig. 2: Gene–sex–age–environment–gender interactions shape the progression of amyotrophic lateral sclerosis (ALS).
Fig. 3: Brain–body interactions are a missing link in fully understanding the pathogenesis of amyotrophic lateral sclerosis (ALS).
Fig. 4: Sex differences in the CNS parenchyma and blood–CNS barriers in the pathogenesis of ALS.

Similar content being viewed by others

References

  1. Gorelick, P. B. & Alter, M. (eds.) Handbook of Neuroepidemiology (Marcel Dekker, 1994). 

  2. McGuire, V., Longstreth, W. T., Koepsell, T. D. & van Belle, G. Incidence of amyotrophic lateral sclerosis in three counties in Western Washington state. Neurology 47, 571–573 (1996).

    CAS  PubMed  Google Scholar 

  3. Abhinav, K. et al. Amyotrophic lateral sclerosis in South-East England: a population-based study. Neuroepidemiology 29, 44–48 (2007).

    CAS  PubMed  Google Scholar 

  4. Chio, A. et al. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology 72, 725–731 (2009).

    CAS  PubMed  Google Scholar 

  5. Vázquez, M. C. et al. Incidence and prevalence of amyotrophic lateral sclerosis in Uruguay: a population-based study. Neuroepidemiology 30, 105–111 (2008).

    PubMed  Google Scholar 

  6. Mehta, P. et al. Prevalence of amyotrophic lateral sclerosis — United States, 2015. MMWR Morb. Mortal. Wkly. Rep. 67, 1285–1289 (2018).

    PubMed  PubMed Central  Google Scholar 

  7. Traynor, B. J. et al. Incidence and prevalence of ALS in Ireland, 1995-1997: a population-based study. Neurology 52, 504 (1999).

    CAS  PubMed  Google Scholar 

  8. Atsuta, N. et al. Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis. J. Neurol. Sci. 276, 163–169 (2009).

    PubMed  Google Scholar 

  9. Nalini, A., Thennarasu, K., Gourie-Devi, M., Shenoy, S. & Kulshreshtha, D. Clinical characteristics and survival pattern of 1153 patients with amyotrophic lateral sclerosis: experience over 30 years from India. J. Neurol. Sci. 272, 60–70 (2008).

    CAS  PubMed  Google Scholar 

  10. Masrori, P. & Van Damme, P. Amyotrophic lateral sclerosis: a clinical review. Eur. J. Neurol. 27, 1918–1929 (2020).

    CAS  PubMed  Google Scholar 

  11. Turner, M. R. et al. The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis. J. Neurol. Sci. 294, 81–85 (2010).

    PubMed  Google Scholar 

  12. Zhang, H., Chen, L., Tian, J. & Fan, D. Disease duration of progression is helpful in identifying isolated bulbar palsy of amyotrophic lateral sclerosis. BMC Neurol. 21, 405 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kiernan, M. C. et al. Amyotrophic lateral sclerosis. Lancet 377, 942–955 (2011).

    CAS  PubMed  Google Scholar 

  14. Strong, M. J. et al. Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph. Lateral Scler. Front. Degener. 18, 153–174 (2017).

    Google Scholar 

  15. Chio, A., Calvo, A., Moglia, C., Mazzini, L. & Mora, G. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J. Neurol. Neurosurg. Psychiatry 82, 740–746 (2011).

    PubMed  Google Scholar 

  16. Eisen, A. & Krieger, C. Amyotrophic Lateral Sclerosis: a Synthesis of Research and Clinical Practice (Cambridge Univ. Press, 1998).

  17. McCombe, P. A. & Henderson, R. D. Effects of gender in amyotrophic lateral sclerosis. Gend. Med. 7, 557–570 (2010).

    PubMed  Google Scholar 

  18. Vlassoff, C. Gender differences in determinants and consequences of health and illness. J. Health Popul. Nutr. 25, 47–61 (2007).

    PubMed  PubMed Central  Google Scholar 

  19. Taylor, J. P., Brown, R. H. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).

    PubMed  PubMed Central  Google Scholar 

  20. Pape, J. A. & Grose, J. H. The effects of diet and sex in amyotrophic lateral sclerosis. Rev. Neurol. 176, 301–315 (2020).

    CAS  PubMed  Google Scholar 

  21. Trojsi, F., D’Alvano, G., Bonavita, S. & Tedeschi, G. Genetics and sex in the pathogenesis of amyotrophic lateral sclerosis (ALS): is there a link? Int. J. Mol. Sci. 21, 3647 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mehta, P. et al. Incidence of amyotrophic lateral sclerosis in the United States, 2014-2016. Amyotroph. Lateral Scler. Frontotemporal Degener. 23, 378–382 (2022).

    PubMed  Google Scholar 

  23. Jun, K. Y. et al. Epidemiology of ALS in Korea using nationwide big data. J. Neurol. Neurosurg. Psychiatry 90, 395–403 (2019).

    PubMed  Google Scholar 

  24. Shahrizaila, N. et al. Amyotrophic lateral sclerosis and motor neuron syndromes in Asia. J. Neurol. Neurosurg. Psychiatry 87, 821–830 (2016).

    CAS  PubMed  Google Scholar 

  25. Manjaly, Z. R. et al. The sex ratio in amyotrophic lateral sclerosis: a population based study. Amyotroph. Lateral Scler. 11, 439–442 (2010).

    PubMed  PubMed Central  Google Scholar 

  26. Marin, B., Gil, J., Preux, P. M., Funalot, B. & Couratier, P. Incidence of amyotrophic lateral sclerosis in the Limousin region of France, 1997–2007. Amyotroph. Lateral Scler. 10, 216–220 (2009).

    PubMed  Google Scholar 

  27. Wolfson, C., Gauvin, D. E., Ishola, F. & Oskoui, M. Global prevalence and incidence of amyotrophic lateral sclerosis: a systematic review. Neurology 101, e613–e623 (2023).

    PubMed  Google Scholar 

  28. Brown, C. A., Lally, C., Kupelian, V. & Flanders, W. D. Estimated prevalence and incidence of amyotrophic lateral sclerosis and SOD1 and C9orf72 genetic variants. Neuroepidemiology 55, 342–353 (2021).

    PubMed  Google Scholar 

  29. Chiò, A. et al. Secular trends of amyotrophic lateral sclerosis: the Piemonte and Valle d’Aosta Register. JAMA Neurol. 74, 1097–1104 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. Newell, M. E., Adhikari, S. & Halden, R. U. Systematic and state-of the science review of the role of environmental factors in amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease. Sci. Total Environ. 817, 152504 (2022).

    CAS  PubMed  Google Scholar 

  31. Andrew, A. S. et al. Risk factors for amyotrophic lateral sclerosis: a regional United States case-control study. Muscle Nerve 63, 52–59 (2021).

    PubMed  Google Scholar 

  32. Goutman, S. A. et al. Avocational exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study. J. Neurol. Sci. 457, 122899 (2024).

    PubMed  Google Scholar 

  33. Walhout, R., Verstraete, E., van den Heuvel, M. P., Veldink, J. H. & van den Berg, L. H. Patterns of symptom development in patients with motor neuron disease. Amyotroph. Lateral Scler. Frontotemporal Degener. 19, 21–28 (2018).

    PubMed  Google Scholar 

  34. Feldman, E. L. et al. Amyotrophic lateral sclerosis. Lancet 400, 1363–1380 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Swinnen, B. & Robberecht, W. The phenotypic variability of amyotrophic lateral sclerosis. Nat. Rev. Neurol. 10, 661–670 (2014).

    PubMed  Google Scholar 

  36. Zhang, H. G., Chen, L., Tang, L., Zhang, N. & Fan, D. S. Clinical features of isolated bulbar palsy of amyotrophic lateral sclerosis in Chinese population. Chin. Med. J. 130, 1768–1772 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Burrell, J. R., Vucic, S. & Kiernan, M. C. Isolated bulbar phenotype of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 12, 283–289 (2011).

    PubMed  Google Scholar 

  38. Raymond, J., Mehta, P., Larson, T., Pioro, E. P. & Horton, D. K. Reproductive history and age of onset for women diagnosed with amyotrophic lateral sclerosis: data from the National ALS Registry: 2010–2018. Neuroepidemiology 55, 416–424 (2021).

    PubMed  Google Scholar 

  39. Grassano, M. et al. Sex differences in amyotrophic lateral sclerosis survival and progression: a multidimensional analysis. Ann. Neurol. https://doi.org/10.1002/ana.26933 (2024).

  40. Pinto, S., Gromicho, M., Oliveira Santos, M. O., Swash, M. & De Carvalho, M. Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern. Amyotroph. Lateral Scler. Frontotemporal Degener. 24, 40–44 (2023).

    CAS  PubMed  Google Scholar 

  41. Fayemendy, P. et al. Hypermetabolism is a reality in amyotrophic lateral sclerosis compared to healthy subjects. J. Neurol. Sci. 420, 117257 (2021).

    PubMed  Google Scholar 

  42. Steyn, F. J. et al. Hypermetabolism in ALS is associated with greater functional decline and shorter survival. J. Neurol. Neurosurg. Psychiatry 89, 1016–1023 (2018).

    PubMed  Google Scholar 

  43. Ferri, A. & Coccurello, R. What is ‘hyper’ in the ALS hypermetabolism? Mediators Inflamm. 2017, 7821672 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. Funalot, B., Desport, J. C., Sturtz, F., Camu, W. & Couratier, P. High metabolic level in patients with familial amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 10, 113–117 (2009).

    CAS  PubMed  Google Scholar 

  45. Rosenfeld, J. & Strong, M. J. Challenges in the understanding and treatment of amyotrophic lateral sclerosis/motor neuron disease. Neurotherapeutics 12, 317–325 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

    CAS  PubMed  Google Scholar 

  47. Corson, L. B., Strain, J. J., Culotta, V. C. & Cleveland, D. W. Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. Proc. Natl Acad. Sci. USA 95, 6361–6366 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Smeyers, J., Banchi, E. G. & Latouche, M. C9ORF72: what it is, what it does, and why it matters. Front. Cell. Neurosci. 15, 661447 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Balendra, R. & Isaacs, A. M. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat. Rev. Neurol. 14, 544–558 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Suk, T. R. & Rousseaux, M. W. C. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol. Neurodegener. 15, 45 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A. & Patel, B. K. Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front. Mol. Neurosci. 12, 25 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chio, A. et al. Extensive genetics of ALS: a population-based study in Italy. Neurology 79, 1983–1989 (2012).

    PubMed  PubMed Central  Google Scholar 

  53. Salmon, K. et al. The importance of offering early genetic testing in everyone with amyotrophic lateral sclerosis. Brain 145, 1207–1210 (2022).

    PubMed  PubMed Central  Google Scholar 

  54. Berdyński, M. et al. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci. Rep. 12, 103 (2022).

    PubMed  PubMed Central  Google Scholar 

  55. Bunton-Stasyshyn, R. K. A., Saccon, R. A., Fratta, P. & Fisher, E. M. C. SOD1 function and its implications for amyotrophic lateral sclerosis pathology: new and renascent themes. Neuroscientist 21, 519–529 (2015).

    CAS  PubMed  Google Scholar 

  56. Saccon, R. A., Bunton-Stasyshyn, R. K. A., Fisher, E. M. C. & Fratta, P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain 136, 2342–2358 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R. & Gitler, A. D. ALS genetics: gains, losses, and implications for future therapies. Neuron 108, 822–842 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Yim, M. B. et al. A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: an enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. Proc. Natl Acad. Sci. USA 93, 5709–5714 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. van Blitterswijk, M., DeJesus-Hernandez, M. & Rademakers, R. How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia. Curr. Opin. Neurol. 25, 689–700 (2012).

    PubMed  PubMed Central  Google Scholar 

  62. Curtis, A. F. et al. Sex differences in the prevalence of genetic mutations in FTD and ALS. Neurology 89, 1633–1642 (2017).

    PubMed  PubMed Central  Google Scholar 

  63. Esselin, F. et al. Clinical phenotype and inheritance in patients with C9ORF72 hexanucleotide repeat expansion: results from a large French cohort. Front. Neurosci. 14, 316 (2020).

    PubMed  PubMed Central  Google Scholar 

  64. Wiesenfarth, M. et al. Clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations. Brain Commun. 5, fcad087 (2023).

    PubMed  PubMed Central  Google Scholar 

  65. Laaksovirta, H. et al. ALS in Finland: major genetic variants and clinical characteristics of patients with and without the C9orf72 hexanucleotide repeat expansion. Neurol. Genet. 8, e665 (2022).

    PubMed  PubMed Central  Google Scholar 

  66. Yusipov, I. et al. Age-related DNA methylation changes are sex-specific: a comprehensive assessment. Aging 12, 24057–24080 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kovtun, I. V., Therneau, T. M. & McMurray, C. T. Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington’s disease gene. Hum. Mol. Genet. 9, 2767–2775 (2000).

    CAS  PubMed  Google Scholar 

  68. Trojsi, F. et al. Comparative analysis of C9orf72 and sporadic disease in a large multicenter ALS population: the effect of male sex on survival of C9orf72 positive patients. Front. Neurosci. 13, 485 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Rooney, J. et al. C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 88, 281 (2017).

    PubMed  Google Scholar 

  70. Murphy, N. A. et al. Age-related penetrance of the C9orf72 repeat expansion. Sci. Rep. 7, 2116 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. Burberry, A. et al. C9orf72 suppresses systemic and neural inflammation induced by gut bacteria. Nature 582, 89–94 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347ra93 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. Ugolino, J. et al. Loss of C9orf72 enhances autophagic activity via deregulated mTOR and TFEB signaling. PLoS Genet. 12, e1006443 (2016).

    PubMed  PubMed Central  Google Scholar 

  74. Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426–438 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cook, C. N. et al. C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Sci. Transl. Med. 12, eabb3774 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Verdone, B. M. et al. A mouse model with widespread expression of the C9orf72-linked glycine–arginine dipeptide displays non-lethal ALS/FTD-like phenotypes. Sci. Rep. 12, 5644 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu, Y. et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90, 521–534 (2016).

    CAS  PubMed  Google Scholar 

  78. Podcasy, J. L. & Epperson, C. N. Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin. Neurosci. 18, 437–446 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Pengo, M. et al. Sex influences clinical phenotype in frontotemporal dementia. Neurol. Sci. 43, 5281–5287 (2022).

    PubMed  PubMed Central  Google Scholar 

  80. McDonald, K. K. et al. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum. Mol. Genet. 20, 1400–1410 (2011).

    CAS  PubMed  Google Scholar 

  81. Buratti, E. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 20, 1774–1784 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Junttila, A. et al. Cerebrospinal fluid TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis patients with and without the C9ORF72 hexanucleotide expansion. Dement. Geriatr. Cogn. Dis. Extra 6, 142–149 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. Lombardi, M. et al. Variability in clinical phenotype in TARDBP mutations: amyotrophic lateral sclerosis case description and literature review. Genes 14, 2309 (2023).

    Google Scholar 

  84. Wegorzewska, I., Bell, S., Cairns, N. J., Miller, T. M. & Baloh, R. H. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Watkins, J. et al. Female sex mitigates motor and behavioural phenotypes in TDP-43Q331K knock-in mice. Sci. Rep. 10, 19220 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Martin, S., Battistini, C. & Sun, J. A gut feeling in amyotrophic lateral sclerosis: microbiome of mice and men. Front. Cell. Infect. Microbiol. 12, 839526 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Guo, Y. et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 1460, 88–95 (2012).

    CAS  PubMed  Google Scholar 

  88. Esmaeili, M. A., Panahi, M., Yadav, S., Hennings, L. & Kiaei, M. Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int. J. Exp. Pathol. 94, 56–64 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Coughlan, K. S., Halang, L., Woods, I. & Prehn, J. H. M. A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice. Dis. Model. Mech. 9, 1029–1037 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Khymenets, O. et al. Role of sex and time of blood sampling in SOD1 and SOD2 expression variability. Clin. Biochem. 41, 1348–1354 (2008).

    CAS  PubMed  Google Scholar 

  91. Tang, L., Ma, Y., Liu, X., Chen, L. & Fan, D. Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history. Transl. Neurodegener. 8, 2 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Chiò, A. et al. ALS phenotype is influenced by age, sex, and genetics. Neurology 94, e802–e810 (2020).

    PubMed  Google Scholar 

  93. Cervetto, C., Frattaroli, D., Maura, G. & Marcoli, M. Motor neuron dysfunction in a mouse model of ALS: gender-dependent effect of P2X7 antagonism. Toxicology 311, 69–77 (2013).

    CAS  PubMed  Google Scholar 

  94. Suzuki, M. et al. Sexual dimorphism in disease onset and progression of a rat model of ALS. Amyotroph. Lateral Scler. 8, 20–25 (2007).

    PubMed  Google Scholar 

  95. Oliván, S. et al. Comparative study of behavioural tests in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Exp. Anim. 64, 147–153 (2015).

    PubMed  Google Scholar 

  96. Pfohl, S. R., Halicek, M. T. & Mitchell, C. S. Characterization of the contribution of genetic background and gender to disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis: a meta-analysis. J. Neuromuscul. Dis. 2, 137–150 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. Ohta, Y. et al. Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis. Hum. Mol. Genet. 25, 4771–4786 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Stam, N. C. et al. Sex-specific behavioural effects of environmental enrichment in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 28, 717–723 (2008).

    PubMed  Google Scholar 

  99. Heiman-Patterson, T. D. et al. Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS. J. Neurol. Sci. 236, 1–7 (2005).

    CAS  PubMed  Google Scholar 

  100. Urushitani, M. et al. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat. Neurosci. 9, 108–118 (2006).

    CAS  PubMed  Google Scholar 

  101. Gros-Louis, F. et al. Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 106, 21777–21782 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Deng, H.-X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Renaud, L., Picher-Martel, V., Codron, P. & Julien, J. P. Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. Acta Neuropathol. Commun. 7, 103 (2019).

    PubMed  PubMed Central  Google Scholar 

  104. Chua, J. P., De Calbiac, H., Kabashi, E. & Barmada, S. J. Autophagy and ALS: mechanistic insights and therapeutic implications. Autophagy 18, 254–282 (2022).

    CAS  PubMed  Google Scholar 

  105. Lin, B. C., Higgins, N. R., Phung, T. H. & Monteiro, M. J. UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD. FEBS J. 289, 6132–6153 (2022).

    CAS  PubMed  Google Scholar 

  106. Higgins, N., Lin, B. & Monteiro, M. J. Lou Gehrig’s disease (ALS): UBQLN2 mutations strike out of phase. Structure 27, 879–881 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Vengoechea, J., David, M. P., Yaghi, S. R., Carpenter, L. & Rudnicki, S. A. Clinical variability and female penetrance in X-linked familial FTD/ALS caused by a P506S mutation in UBQLN2. Amyotroph. Lateral Scler. Frontotemporal Degener. 14, 615–619 (2013).

    CAS  PubMed  Google Scholar 

  108. Gkazi, S. A. et al. Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia. Neurobiol. Aging 73, 229.e5–229.e9 (2019).

    CAS  PubMed  Google Scholar 

  109. Alexander, E. J. et al. Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation. Proc. Natl Acad. Sci. USA 115, E11485–E11494 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dao, T. P. et al. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell 69, 965–978.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gilpin, K. M., Chang, L. & Monteiro, M. J. ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1. Hum. Mol. Genet. 24, 2565–2577 (2015).

    CAS  PubMed  Google Scholar 

  112. Picher-Martel, V., Dutta, K., Phaneuf, D., Sobue, G. & Julien, J. P. Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells. Mol. Brain 8, 71 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. Picher-Martel, V., Renaud, L., Bareil, C. & Julien, J. P. Neuronal expression of UBQLN2P497H exacerbates TDP-43 pathology in TDP-43G348C mice through interaction with ubiquitin. Mol. Neurobiol. 56, 4680–4696 (2019).

    CAS  PubMed  Google Scholar 

  114. Malik, A. M. & Barmada, S. J. Matrin 3 in neuromuscular disease: physiology and pathophysiology. JCI Insight 6, e143948 (2021).

    PubMed  PubMed Central  Google Scholar 

  115. Iradi, M. C. G. et al. Characterization of gene regulation and protein interaction networks for Matrin 3 encoding mutations linked to amyotrophic lateral sclerosis and myopathy. Sci. Rep. 8, 4049 (2018).

    PubMed  PubMed Central  Google Scholar 

  116. Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Cassel, J. A. & Reitz, A. B. Ubiquilin-2 (UBQLN2) binds with high affinity to the C-terminal region of TDP-43 and modulates TDP-43 levels in H4 cells: characterization of inhibition by nucleic acids and 4-aminoquinolines. Biochim. Biophys. Acta 1834, 964–971 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Strong, M. J. Revisiting the concept of amyotrophic lateral sclerosis as a multisystems disorder of limited phenotypic expression. Curr. Opin. Neurol. 30, 599–607 (2017).

    PubMed  Google Scholar 

  119. Oliva, M. et al. The impact of sex on gene expression across human tissues. Science 369, eaba3066 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Ruigrok, A. N. V. et al. A meta-analysis of sex differences in human brain structure. Neurosci. Biobehav. Rev. 39, 34–50 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Weis, S. et al. Sex classification by resting state brain connectivity. Cereb. Cortex 30, 824–835 (2020).

    PubMed  Google Scholar 

  122. Renga, V. Brain connectivity and network analysis in amyotrophic lateral sclerosis. Neurol. Res. Int. 2022, 1838682 (2022).

    PubMed  PubMed Central  Google Scholar 

  123. Bede, P., Elamin, M., Byrne, S. & Hardiman, O. Sexual dimorphism in ALS: exploring gender-specific neuroimaging signatures. Amyotroph. Lateral Scler. Front. Degener. 15, 235–243 (2014).

    Google Scholar 

  124. Pfefferbaum, A. et al. Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging. Magn. Reson. Med. 44, 259–268 (2000).

    CAS  PubMed  Google Scholar 

  125. Trojsi, F. et al. Between-sex variability of resting state functional brain networks in amyotrophic lateral sclerosis (ALS). J. Neural Transm. 128, 1881–1897 (2021).

    PubMed  Google Scholar 

  126. Workman, M. J. et al. Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects. Neuron 111, 1191–1204.e5 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Stoklund Dittlau, K. & Freude, K. Astrocytes: the stars in neurodegeneration? Biomolecules 14, 289 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Xie, M., Pallegar, P. N., Parusel, S., Nguyen, A. T. & Wu, L. J. Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms. Mol. Neurodegener. 18, 75 (2023).

    PubMed  PubMed Central  Google Scholar 

  129. Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Boillée, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).

    PubMed  Google Scholar 

  131. Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).

    CAS  PubMed  Google Scholar 

  132. Yamanaka, K. et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl Acad. Sci. USA 105, 7594–7599 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Amateau, S. K. & McCarthy, M. M. Sexual differentiation of astrocyte morphology in the developing rat preoptic area. J. Neuroendocrinol. 14, 904–910 (2002).

    CAS  PubMed  Google Scholar 

  134. Arias, C. et al. Sex and estrous cycle-dependent differences in glial fibrillary acidic protein immunoreactivity in the adult rat hippocampus. Horm. Behav. 55, 257–263 (2009).

    CAS  PubMed  Google Scholar 

  135. Collado, P., Beyer, C., Hutchison, J. B. & Holman, S. D. Hypothalamic distribution of astrocytes is gender-related in Mongolian gerbils. Neurosci. Lett. 184, 86–89 (1995).

    CAS  PubMed  Google Scholar 

  136. Conejo, N. M. et al. Influence of gonadal steroids on the glial fibrillary acidic protein‐immunoreactive astrocyte population in young rat hippocampus. J. Neurosci. Res. 79, 488–494 (2005).

    CAS  PubMed  Google Scholar 

  137. Garcia-Segura, L. M., Dueñas, M., Busiguina, S., Naftolin, F. & Chowen, J. A. Gonadal hormone regulation of neuronal-glial interactions in the developing neuroendocrine hypothalamus. J. Steroid Biochem. Mol. Biol. 53, 293–298 (1995).

    CAS  PubMed  Google Scholar 

  138. Garcia-Segura, L. M. et al. The distribution of glial fibrillary acidic protein in the adult rat brain is influenced by the neonatal levels of sex steroids. Brain Res. 456, 357–363 (1988).

    CAS  PubMed  Google Scholar 

  139. Kuo, J., Hamid, N., Bondar, G., Prossnitz, E. R. & Micevych, P. Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes. J. Neurosci. 30, 12950–12957 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Rasia-Filho, A. A., Xavier, L. L., dos Santos, P., Gehlen, G. & Achaval, M. Glial fibrillary acidic protein immunodetection and immunoreactivity in the anterior and posterior medial amygdala of male and female rats. Brain Res. Bull. 58, 67–75 (2002).

    CAS  PubMed  Google Scholar 

  141. Suárez, I., Bodega, G., Rubio, M. & Fernández, B. Sexual dimorphism in the hamster cerebellum demonstrated by glial fibrillary acidic protein (GFAP) and vimentin immunoreactivity. Glia 5, 10–16 (1992).

    PubMed  Google Scholar 

  142. Suárez, I., Bodega, G., Rubio, M. & Fernandez, B. Sexual dimorphism in the distribution of glial fibrillary acidic protein in the supraoptic nucleus of the hamster. J. Anat. 178, 79–82 (1991).

    PubMed  PubMed Central  Google Scholar 

  143. Dion-Albert, L. et al. Sex differences in the blood–brain barrier: implications for mental health. Front. Neuroendocrinol. 65, 100989 (2022).

    CAS  PubMed  Google Scholar 

  144. Weber, C. M. & Clyne, A. M. Sex differences in the blood–brain barrier and neurodegenerative diseases. APL Bioeng. 5, 011509 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Liu, M., Hurn, P. D., Roselli, C. E. & Alkayed, N. J. Role of P450 aromatase in sex-specific astrocytic cell death. J. Cereb. Blood Flow Metab. 27, 135–141 (2007).

    CAS  PubMed  Google Scholar 

  146. Humphrey, J. et al. Integrative transcriptomic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes. Nat. Neurosci. 26, 150–162 (2023).

    CAS  PubMed  Google Scholar 

  147. Nave, K. A., Asadollahi, E. & Sasmita, A. Expanding the function of oligodendrocytes to brain energy metabolism. Curr. Opin. Neurobiol. 83, 102782 (2023).

    CAS  PubMed  Google Scholar 

  148. Yasuda, K. et al. Sex-specific differences in transcriptomic profiles and cellular characteristics of oligodendrocyte precursor cells. Stem Cell Res. 46, 101866 (2020).

    CAS  PubMed  Google Scholar 

  149. Villa, A., Della Torre, S. & Maggi, A. Sexual differentiation of microglia. Front. Neuroendocrinol. 52, 156–164 (2019).

    PubMed  Google Scholar 

  150. Kodama, L. & Gan, L. Do microglial sex differences contribute to sex differences in neurodegenerative diseases? Trends Mol. Med. 25, 741–749 (2019).

    PubMed  Google Scholar 

  151. Sala Frigerio, C. et al. The major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 27, 1293–1306.e6 (2019).

    CAS  PubMed  Google Scholar 

  152. Gomes, L. C. et al. Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target. Preprint at bioRxiv https://doi.org/10.1101/2023.08.14.553180 (2023).

  153. Abbott, N. J. Astrocyte–endothelial interactions and blood–brain barrier permeability. J. Anat. 200, 629–638 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Daneman, R. & Prat, A. The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).

    PubMed  PubMed Central  Google Scholar 

  155. Muldoon, L. L. et al. Immunologic privilege in the central nervous system and the blood–brain barrier. J. Cereb. Blood Flow Metab. 33, 13–21 (2013).

    CAS  PubMed  Google Scholar 

  156. Prockop, L. D., Naidu, K. A., Binard, J. E. & Ransohoff, J. Selective permeability of [3H]-D-mannitol and [14C]-carboxyl-inulin across the blood-brain barrier and blood-spinal cord barrier in the rabbit. J. Spinal Cord Med. 18, 221–226 (1995).

    CAS  PubMed  Google Scholar 

  157. Pan, W., Banks, W. A. & Kastin, A. J. Permeability of the blood-brain and blood-spinal cord barriers to interferons. J. Neuroimmunol. 76, 105–111 (1997).

    CAS  PubMed  Google Scholar 

  158. Winkler, E. A. et al. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc. Natl Acad. Sci. USA 111, E1035–E1042 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Yoon, H., Walters, G., Paulsen, A. R. & Scarisbrick, I. A. Astrocyte heterogeneity across the brain and spinal cord occurs developmentally, in adulthood and in response to demyelination. PLoS ONE 12, e0180697 (2017).

    PubMed  PubMed Central  Google Scholar 

  160. Garbuzova-Davis, S. et al. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 1157, 126–137 (2007).

    CAS  PubMed  Google Scholar 

  161. Zhong, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Miyazaki, K. et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J. Neurosci. Res. 89, 718–728 (2011).

    CAS  PubMed  Google Scholar 

  163. Steinruecke, M. et al. Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: proposed mechanisms and clinical implications. J. Cereb. Blood Flow Metab. 43, 642–654 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Garbuzova-Davis, S. et al. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res. 1398, 113–25 (2011).

    CAS  PubMed  Google Scholar 

  165. Donnenfeld, H., Kascsak, R. J. & Bartfeld, H. Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J. Neuroimmunol. 6, 51–57 (1984).

    CAS  PubMed  Google Scholar 

  166. Henkel, J. S. et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55, 221–235 (2004).

    CAS  PubMed  Google Scholar 

  167. Yamadera, M. et al. Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 393–401 (2015).

    PubMed  Google Scholar 

  168. Garbuzova-Davis, S. et al. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 1469, 114–128 (2012).

    CAS  PubMed  Google Scholar 

  169. Dalla, C., Pavlidi, P., Sakelliadou, D. G., Grammatikopoulou, T. & Kokras, N. Sex differences in blood–brain barrier transport of psychotropic drugs. Front. Behav. Neurosci. 16, 844916 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Alarcan, H. et al. Implication of central nervous system barrier impairment in amyotrophic lateral sclerosis: gender-related difference in patients. Int. J. Mol. Sci. 24, 11196 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Hakim, M. A., Chum, P. P., Buchholz, J. N. & Behringer, E. J. Aging alters cerebrovascular endothelial GPCR and K+ channel function: divergent role of biological sex. J. Gerontol. A 75, 2064–2073 (2020).

    CAS  Google Scholar 

  172. Bauersachs, J. et al. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 94, 3341–3347 (1996).

    CAS  PubMed  Google Scholar 

  173. Min, J. 17β-Estradiol-stimulated eNOS gene transcriptional activation is regulated through the estrogen-responsive element in eNOS promoter. Biotechnol. Bioprocess. Eng. 12, 446–449 (2007).

    CAS  Google Scholar 

  174. Zhang, L., Papadopoulos, P. & Hamel, E. Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer’s disease. Br. J. Pharmacol. 170, 661–670 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Marrelli, S. P., O’Neil, R. G., Brown, R. C. & Bryan, R. M. PLA 2 and TRPV4 channels regulate endothelial calcium in cerebral arteries. Am. J. Physiol. Circ. Physiol. 292, H1390–H1397 (2007).

    CAS  Google Scholar 

  176. Longden, T. A., Hill-Eubanks, D. C. & Nelson, M. T. Ion channel networks in the control of cerebral blood flow. J. Cereb. Blood Flow Metab. 36, 492–512 (2016).

    CAS  PubMed  Google Scholar 

  177. Stoica, R. et al. Ca2+ homeostasis in brain microvascular endothelial cells. Int. Rev. Cell Mol. Biol. 362, 55–110 (2021).

    CAS  PubMed  Google Scholar 

  178. Gur, R. C. et al. Sex differences in regional cerebral glucose metabolism during a resting state. Science 267, 528–531 (1995).

    CAS  PubMed  Google Scholar 

  179. Lerskiatiphanich, T., Marallag, J. & Lee, J. Glucose metabolism in amyotrophic lateral sclerosis: it is bitter-sweet. Neural Regen. Res. 17, 1975 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Tefera, T. W., Steyn, F. J., Ngo, S. T. & Borges, K. CNS glucose metabolism in amyotrophic lateral sclerosis: a therapeutic target? Cell Biosci. 11, 14 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Clyne, A. M. Endothelial response to glucose: dysfunction, metabolism, and transport. Biochem. Soc. Trans. 49, 313–325 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Ahmed, R. M., Steyn, F. & Dupuis, L. Hypothalamus and weight loss in amyotrophic lateral sclerosis. Handb. Clin. Neurol. 180, 327–338 (2021).

    PubMed  Google Scholar 

  183. Kawachi, T. et al. Gender differences in cerebral glucose metabolism: a PET study. J. Neurol. Sci. 199, 79–83 (2002).

    CAS  PubMed  Google Scholar 

  184. Mukai, E., Fujimoto, S. & Inagaki, N. Role of reactive oxygen species in glucose metabolism disorder in diabetic pancreatic β-cells. Biomolecules 12, 1228 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Ventura-Clapier, R. et al. Mitochondria: a central target for sex differences in pathologies. Clin. Sci. 131, 803–822 (2017).

    CAS  Google Scholar 

  186. Cacabelos, D. et al. Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS. Acta Neuropathol. Commun. 4, 3 (2016).

    PubMed  PubMed Central  Google Scholar 

  187. Damiano, M. et al. Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J. Neurochem. 96, 1349–1361 (2006).

    CAS  PubMed  Google Scholar 

  188. Lalancette-Hebert, M., Sharma, A., Lyashchenko, A. K. & Shneider, N. A. Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS. Proc. Natl Acad. Sci. USA 113, E8316–E8325 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Yadav, A. et al. A cellular taxonomy of the adult human spinal cord. Neuron 111, 328–344.e7 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Pontifex, C. S., Zaman, M., Fanganiello, R. D., Shutt, T. E. & Pfeffer, G. Valosin-containing protein (VCP): a review of its diverse molecular functions and clinical phenotypes. Int. J. Mol. Sci. 25, 5633 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Inglis, J. G. & Gabriel, D. A. Sex differences in the modulation of the motor unit discharge rate leads to reduced force steadiness. Appl. Physiol. Nutr. Metab. 46, 1065–1072 (2021).

    CAS  PubMed  Google Scholar 

  192. Taylor, C. A., Kopicko, B. H., Negro, F. & Thompson, C. K. Sex differences in the detection of motor unit action potentials identified using high-density surface electromyography. J. Electromyogr. Kinesiol. 65, 102675 (2022).

    PubMed  PubMed Central  Google Scholar 

  193. Fishman, R. B. & Breedlove, S. M. Local perineal implants of anti-androgen block masculinization of the spinal nucleus of the bulbocavernosus. Brain Res. Dev. Brain Res. 70, 283–286 (1992).

    CAS  PubMed  Google Scholar 

  194. Omar, A., Marwaha, K. & Bollu, P. C. Physiology, Neuromuscular Junction (StatPearls, 2024).

  195. Verma, S. et al. Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Mol. Neurobiol. 59, 1502–1527 (2022).

    CAS  PubMed  Google Scholar 

  196. Armon, C. & Brandstater, M. E. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve 22, 1571–1575 (1999).

    CAS  PubMed  Google Scholar 

  197. Martineau, É., Di Polo, A., Vande Velde, C. & Robitaille, R. Sex-specific differences in motor-unit remodeling in a mouse model of ALS. eNeuro 7, https://doi.org/10.1523/ENEURO.0388-19.2020 (2020).

  198. Shefner, J. M. et al. Skeletal muscle in amyotrophic lateral sclerosis. Brain 146, 4425–4436 (2023).

    PubMed  PubMed Central  Google Scholar 

  199. Badu-Mensah, A., Guo, X., Nimbalkar, S., Cai, Y. & Hickman, J. J. ALS mutations in both human skeletal muscle and motoneurons differentially affects neuromuscular junction integrity and function. Biomaterials 289, 121752 (2022).

    CAS  PubMed  Google Scholar 

  200. Dobrowolny, G. et al. Muscle expression of SOD1G93A triggers the dismantlement of neuromuscular junction via PKC-theta. Antioxid. Redox Signal. 28, 1105–1119 (2018).

    CAS  PubMed  Google Scholar 

  201. Steyn, F. J. et al. Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis. Brain Commun. 2, fcaa154 (2020).

    PubMed  PubMed Central  Google Scholar 

  202. Palamiuc, L. et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol. Med. 7, 526–546 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Haizlip, K. M., Harrison, B. C. & Leinwand, L. A. Sex-based differences in skeletal muscle kinetics and fiber-type composition. Physiology 30, 30–39 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. van Wessel, T., de Haan, A., van der Laarse, W. J. & Jaspers, R. T. The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism? Eur. J. Appl. Physiol. 110, 665–694 (2010).

    PubMed  PubMed Central  Google Scholar 

  205. Anderson, E. J. & Neufer, P. D. Type II skeletal myofibers possess unique properties that potentiate mitochondrial H2O2 generation. Am. J. Physiol. Cell Physiol. 290, C844–C851 (2006).

    CAS  PubMed  Google Scholar 

  206. Pegoraro, V., Merico, A. & Angelini, C. Micro-RNAs in ALS muscle: differences in gender, age at onset and disease duration. J. Neurol. Sci. 380, 58–63 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Gomes, B. C. et al. Differential expression of miRNAs in amyotrophic lateral sclerosis patients. Mol. Neurobiol. 60, 7104–7117 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Zhang, Z., Jin, A. & Yan, D. MicroRNA-206 contributes to the progression of steroid-induced avascular necrosis of the femoral head by inducing osteoblast apoptosis by suppressing programmed cell death 4. Mol. Med. Rep. 17, 801–808 (2018).

    CAS  PubMed  Google Scholar 

  209. Casola, I. et al. Circulating myomiRs in muscle denervation: from surgical to ALS pathological condition. Cells 10, 2043 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Abdelhak, A. et al. In vivo assessment of retinal vessel pathology in amyotrophic lateral sclerosis. J. Neurol. 265, 949–953 (2018).

    CAS  PubMed  Google Scholar 

  211. Kolde, G., Bachus, R. & Ludolph, A. Skin involvement in amyotrophic lateral sclerosis. Lancet 347, 1226–1227 (1996).

    CAS  PubMed  Google Scholar 

  212. Buckley, A. F. & Bossen, E. H. Skeletal muscle microvasculature in the diagnosis of neuromuscular disease. J. Neuropathol. Exp. Neurol. 72, 906–918 (2013).

    PubMed  Google Scholar 

  213. Saul, J. et al. Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 8, 92 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).

    CAS  PubMed  Google Scholar 

  215. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    CAS  PubMed  Google Scholar 

  216. Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Rosenbohm, A. et al. Cardiac findings in amyotrophic lateral sclerosis: a magnetic resonance imaging study. Front. Neurol. 8, 479 (2017).

    PubMed  PubMed Central  Google Scholar 

  218. Xu, K., Ji, H. & Hu, N. Cardiovascular comorbidities in amyotrophic lateral sclerosis: a systematic review. J. Clin. Neurosci. 96, 43–49 (2022).

    PubMed  Google Scholar 

  219. Hu, N. & Ji, H. Medications on hypertension, hyperlipidemia, diabetes, and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol. Sci. 43, 5189–5199 (2022).

    PubMed  Google Scholar 

  220. St. Pierre, S. R., Peirlinck, M. & Kuhl, E. Sex matters: a comprehensive comparison of female and male hearts. Front. Physiol. 13, 831179 (2022).

    Google Scholar 

  221. Gur, R. C. et al. Sex and handedness differences in cerebral blood flow during rest and cognitive activity. Science 217, 659–661 (1982).

    CAS  PubMed  Google Scholar 

  222. Rodriguez, G., Warkentin, S., Risberg, J. & Rosadini, G. Sex differences in regional cerebral blood flow. J. Cereb. Blood Flow Metab. 8, 783–789 (1988).

    CAS  PubMed  Google Scholar 

  223. Satterthwaite, T. D. et al. Impact of puberty on the evolution of cerebral perfusion during adolescence. Proc. Natl Acad. Sci. USA 111, 8643–8648 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Tontisirin, N. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics 119, e610–e615 (2007).

    PubMed  Google Scholar 

  225. Monteiro, J. N. in Essentials of Neuroanesthesia (ed. Prabhakar, H.) 815–825 (Elsevier, 2017).

  226. Deegan, B. M. et al. Elderly women regulate brain blood flow better than men do. Stroke 42, 1988–1993 (2011).

    PubMed  PubMed Central  Google Scholar 

  227. Vavilala, M. S. et al. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr. Res. 58, 574–578 (2005).

    PubMed  PubMed Central  Google Scholar 

  228. Schreiber, S. et al. Brain vascular health in ALS is mediated through motor cortex microvascular integrity. Cells 12, 957 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Chen, Y. et al. Difference in leukocyte composition between women before and after menopausal age, and distinct sexual dimorphism. PLoS ONE 11, e0162953 (2016).

    PubMed  PubMed Central  Google Scholar 

  230. Murdock, B. J., Goutman, S. A., Boss, J., Kim, S. & Feldman, E. L. Amyotrophic lateral sclerosis survival associates with neutrophils in a sex-specific manner. Neurol. Neuroimmunol. Neuroinflamm. 8, e953 (2021).

    PubMed  PubMed Central  Google Scholar 

  231. Lehman, H. K. & Segal, B. H. The role of neutrophils in host defense and disease. J. Allergy Clin. Immunol. 145, 1535–1544 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Janeway, C. A. How the immune system protects the host from infection. Microbes Infect. 3, 1167–1171 (2001).

    CAS  PubMed  Google Scholar 

  233. Bongen, E. et al. Sex differences in the blood transcriptome identify robust changes in immune cell proportions with aging and influenza infection. Cell Rep. 29, 1961–1973.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. McCombe, P., Greer, J. & Mackay, I. Sexual dimorphism in autoimmune disease. Curr. Mol. Med. 9, 1058–1079 (2009).

    CAS  PubMed  Google Scholar 

  235. Santiago, J. A., Quinn, J. P. & Potashkin, J. A. Network analysis identifies sex-specific gene expression changes in blood of amyotrophic lateral sclerosis patients. Int. J. Mol. Sci. 22, 7150 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Beers, D. R. et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2, e89530 (2017).

    PubMed  PubMed Central  Google Scholar 

  237. Beers, D. R. & Appel, S. H. Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies. Lancet Neurol. 18, 211–220 (2019).

    CAS  PubMed  Google Scholar 

  238. Zhao, W., Beers, D. R., Liao, B., Henkel, J. S. & Appel, S. H. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol. Dis. 48, 418–428 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Beckmann, L. et al. Regulatory T cells contribute to sexual dimorphism in neonatal hypoxic-ischemic brain injury. Stroke 53, 381–390 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT03241784 (2018).

  241. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04055623 (2021).

  242. Boddy, S. L. et al. The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med. 19, 13 (2021).

    PubMed  PubMed Central  Google Scholar 

  243. Sun, J., Huang, T., Debelius, J. W. & Fang, F. Gut microbiome and amyotrophic lateral sclerosis: a systematic review of current evidence. J. Intern. Med. 290, 758–788 (2021).

    PubMed  Google Scholar 

  244. Mercedes Prudencio. The effects of ALS on the digestive system. Target ALS https://www.targetals.org/2022/08/25/the-effects-of-als-on-the-digestive-system/ (2015).

  245. Toepfer, C., Folwaczny, A., Klauser & RL, M. Gastrointestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Mot. Neuron Disord. 1, 15–19 (2000).

    Google Scholar 

  246. Kim, Y. S., Unno, T., Kim, B. Y. & Park, M. S. Sex differences in gut microbiota. World J. Mens Health 38, 48 (2020).

    PubMed  Google Scholar 

  247. Schroeder, B. O. & Bäckhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).

    CAS  PubMed  Google Scholar 

  248. Martin, C. R., Osadchiy, V., Kalani, A. & Mayer, E. A. The brain-gut-microbiome axis. Cell. Mol. Gastroenterol. Hepatol. 6, 133–148 (2018).

    PubMed  PubMed Central  Google Scholar 

  249. Thaiss, C. A., Zmora, N., Levy, M. & Elinav, E. The microbiome and innate immunity. Nature 535, 65–74 (2016).

    CAS  PubMed  Google Scholar 

  250. Wang, J., Zhu, N., Su, X., Gao, Y. & Yang, R. Gut-microbiota-derived metabolites maintain gut and systemic immune homeostasis. Cells 12, 793 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Cryan, J. F. et al. The microbiota-gut-brain axis. Physiol. Rev. 99, 1877–2013 (2019).

    CAS  PubMed  Google Scholar 

  252. Rizzetto, L., Fava, F., Tuohy, K. M. & Selmi, C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: the role of sex. J. Autoimmun. 92, 12–34 (2018).

    CAS  PubMed  Google Scholar 

  253. Loh, J. S. et al. Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct. Target. Ther. 9, 37 (2024).

    PubMed  PubMed Central  Google Scholar 

  254. Aburto, M. R. & Cryan, J. F. Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis. Nat. Rev. Gastroenterol. Hepatol. 21, 222–247 (2024).

    PubMed  Google Scholar 

  255. Mazzini, L. et al. Potential role of gut microbiota in ALS pathogenesis and possible novel therapeutic strategies. J. Clin. Gastroenterol. 52, S68–S70 (2018).

    CAS  PubMed  Google Scholar 

  256. Kim, H. S. et al. Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset. BMC Neurol. 22, 62 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Rowin, J., Xia, Y., Jung, B. & Sun, J. Gut inflammation and dysbiosis in human motor neuron disease. Physiol. Rep. 5, e13443 (2017).

    PubMed  PubMed Central  Google Scholar 

  258. Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).

    CAS  PubMed  Google Scholar 

  259. Wu, S., Yi, J., Zhang, Y., Zhou, J. & Sun, J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol. Rep. 3, e12356 (2015).

    PubMed  PubMed Central  Google Scholar 

  260. Zhang, Y. et al. Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clin. Ther. 39, 322–336 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Hatzipetros, T. et al. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 1584, 59–72 (2014).

    CAS  PubMed  Google Scholar 

  262. Guo, K. et al. Gut microbiome correlates with plasma lipids in amyotrophic lateral sclerosis. Brain 147, 665–679 (2023).

    Google Scholar 

  263. Popat, R. A. et al. Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology 27, 117–121 (2006).

    PubMed  Google Scholar 

  264. Choi, C. I. et al. Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice. J. Neurol. Sci. 268, 40–47 (2008).

    CAS  PubMed  Google Scholar 

  265. Gargiulo-Monachelli, G. et al. Circulating gonadal and adrenal steroids in amyotrophic lateral sclerosis: possible markers of susceptibility and outcome. Horm. Metab. Res. 46, 433–439 (2014).

    CAS  PubMed  Google Scholar 

  266. Militello, A. et al. The serum level of free testosterone is reduced in amyotrophic lateral sclerosis. J. Neurol. Sci. 195, 67–70 (2002).

    CAS  PubMed  Google Scholar 

  267. Kim, H. J., Magranè, J., Starkov, A. A. & Manfredi, G. The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain 135, 2865–2874 (2012).

    PubMed  PubMed Central  Google Scholar 

  268. Groeneveld, G. J. et al. Ovariectomy and 17β-estradiol modulate disease progression of a mouse model of ALS. Brain Res. 1021, 128–131 (2004).

    CAS  PubMed  Google Scholar 

  269. Yoo, Y. E. & Ko, C. P. Dihydrotestosterone ameliorates degeneration in muscle, axons and motoneurons and improves motor function in amyotrophic lateral sclerosis model mice. PLoS ONE 7, e37258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. McLeod, V. M. et al. Androgen receptor antagonism accelerates disease onset in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Br. J. Pharmacol. 176, 2111–2130 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. Aggarwal, T. et al. Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis. Neurobiol. Aging 35, 1929–1938 (2014).

    CAS  PubMed  Google Scholar 

  272. Brannvall, K. Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation. Mol. Cell. Neurosci. 21, 512–520 (2002).

    CAS  PubMed  Google Scholar 

  273. Charalampopoulos, I., Remboutsika, E., Margioris, A. N. & Gravanis, A. Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol. Metab. 19, 300–307 (2008).

    CAS  PubMed  Google Scholar 

  274. Garcia-Segura, L. M. & Melcangi, R. C. Steroids and glial cell function. Glia 54, 485–498 (2006).

    PubMed  Google Scholar 

  275. Garcia-Segura, L. M., Diz-Chaves, Y., Perez-Martin, M. & Darnaudéry, M. Estradiol, insulin-like growth factor-I and brain aging. Psychoneuroendocrinology 32, S57–S61 (2007).

    CAS  PubMed  Google Scholar 

  276. Brann, D. W., Dhandapani, K., Wakade, C., Mahesh, V. B. & Khan, M. M. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72, 381–405 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Barron, A. M., Fuller, S. J., Verdile, G. & Martins, R. N. Reproductive hormones modulate oxidative stress in Alzheimer’s disease. Antioxid. Redox Signal. 8, 2047–2059 (2006).

    CAS  PubMed  Google Scholar 

  278. Prokai, L. & Simpkins, J. W. Structure–nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds. Pharmacol. Ther. 114, 1–12 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Gayard, M. et al. AMPK alpha 1-induced RhoA phosphorylation mediates vasoprotective effect of estradiol. Arterioscler. Thromb. Vasc. Biol. 31, 2634–2642 (2011).

    CAS  PubMed  Google Scholar 

  280. Cunha-Oliveira, T. et al. Oxidative stress in amyotrophic lateral sclerosis: pathophysiology and opportunities for pharmacological intervention. Oxid. Med. Cell. Longev. 2020, 5021694 (2020).

    PubMed  PubMed Central  Google Scholar 

  281. Kakaroubas, N., Brennan, S., Keon, M. & Saksena, N. K. Pathomechanisms of blood-brain barrier disruption in ALS. Neurosci. J. 2019, 2537698 (2019).

    PubMed  PubMed Central  Google Scholar 

  282. Yan, L. et al. Effects of ovariectomy in an hSOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS). Med. Sci. Monit. 24, 678–686 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Brinton, R. D., Yao, J., Yin, F., Mack, W. J. & Cadenas, E. Perimenopause as a neurological transition state. Nat. Rev. Endocrinol. 11, 393–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  284. Zhao, L., Mao, Z., Woody, S. K. & Brinton, R. D. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer’s disease. Neurobiol. Aging 42, 69–79 (2016).

    PubMed  PubMed Central  Google Scholar 

  285. Hammond, J. et al. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J. Neurochem. 77, 1319–1326 (2001).

    CAS  PubMed  Google Scholar 

  286. Byers, J. S. et al. Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury. J. Comp. Neurol. 520, 2683–2696 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Hamson, D. K. et al. Androgens increase survival of adult-born neurons in the dentate gyrus by an androgen receptor-dependent mechanism in male rats. Endocrinology 154, 3294–3304 (2013).

    CAS  PubMed  Google Scholar 

  288. Hayes-Punzo, A. et al. Gonadectomy and dehydroepiandrosterone (DHEA) do not modulate disease progression in the G93A mutant SOD1 rat model of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 13, 311–314 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Baulieu, E. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 23, 963–987 (1998).

    CAS  PubMed  Google Scholar 

  290. Lyraki, R. & Schedl, A. The sexually dimorphic adrenal cortex: implications for adrenal disease. Int. J. Mol. Sci. 22, 4889 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  291. Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002).

    CAS  PubMed  Google Scholar 

  292. Ishihara, H., Kanda, F., Nishio, H., Sumino, K. & Chihara, K. Clinical features and skewed X-chromosome inactivation in female carriers of X-linked recessive spinal and bulbar muscular atrophy. J. Neurol. 248, 856–860 (2001).

    CAS  PubMed  Google Scholar 

  293. Mariotti, C. et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul. Disord. 10, 391–397 (2000).

    CAS  PubMed  Google Scholar 

  294. Schmidt, B. J., Greenberg, C. R., Allingham-Hawkins, D. J. & Spriggs, E. L. Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 59, 770–772 (2002).

    PubMed  Google Scholar 

  295. Hashizume, A. et al. Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials. J. Neurol. 266, 1211–1221 (2019).

    CAS  PubMed  Google Scholar 

  296. Uhart, M., Chong, R., Oswald, L., Lin, P. & Wand, G. Gender differences in hypothalamic–pituitary–adrenal (HPA) axis reactivity. Psychoneuroendocrinology 31, 642–652 (2006).

    CAS  PubMed  Google Scholar 

  297. Heck, A. L. & Handa, R. J. Sex differences in the hypothalamic–pituitary–adrenal axis’ response to stress: an important role for gonadal hormones. Neuropsychopharmacology 44, 45–58 (2019).

    CAS  PubMed  Google Scholar 

  298. Patacchioli, F. R. et al. Adrenal dysregulation in amyotrophic lateral sclerosis. J. Endocrinol. Invest. 26, RC23–RC25 (2003).

    CAS  PubMed  Google Scholar 

  299. Feneberg, E. et al. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis. Neurology 90, e22–e30 (2018).

    CAS  PubMed  Google Scholar 

  300. Skillbäck, T. et al. Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity. Alzheimers Dement. 13, e12141 (2021).

    Google Scholar 

  301. Gaiani, A. et al. Diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis. JAMA Neurol. 74, 525 (2017).

    PubMed  PubMed Central  Google Scholar 

  302. Verde, F. et al. Phenotypic correlates of serum neurofilament light chain levels in amyotrophic lateral sclerosis. Front. Aging Neurosci. 15, 1132808 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Fenton, A. et al. Glomerular filtration rate: new age- and gender-specific reference ranges and thresholds for living kidney donation. BMC Nephrol. 19, 336 (2018).

    PubMed  PubMed Central  Google Scholar 

  304. Boylan, K. et al. Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J. Neurochem. 111, 1182–1191 (2009).

    CAS  PubMed  Google Scholar 

  305. Frutiger, K., Lukas, T. J., Gorrie, G., Ajroud-Driss, S. & Siddique, T. Gender difference in levels of Cu/Zn superoxide dismutase (SOD1) in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 9, 184–187 (2008).

    CAS  PubMed  Google Scholar 

  306. Zamani, A. et al. Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis. Transl. Neurodegener. 11, 17 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Hirose, M. et al. Stagnation of glymphatic interstitial fluid flow and delay in waste clearance in the SOD1-G93A mouse model of ALS. Neurosci. Res. 171, 74–82 (2021).

    CAS  PubMed  Google Scholar 

  308. Liu, S. et al. Glymphatic dysfunction in patients with early-stage amyotrophic lateral sclerosis. Brain 147, 100–108 (2024).

    PubMed  Google Scholar 

  309. Shao, C. et al. Comprehensive analysis of individual variation in the urinary proteome revealed significant gender differences. Mol. Cell. Proteom. 18, 1110–1122 (2019).

    CAS  Google Scholar 

  310. Sharygin, D., Koniaris, L. G., Wells, C., Zimmers, T. A. & Hamidi, T. Role of CD14 in human disease. Immunology 169, 260–270 (2023).

    CAS  PubMed  Google Scholar 

  311. Shive, C. L., Jiang, W., Anthony, D. D. & Lederman, M. M. Soluble CD14 is a nonspecific marker of monocyte activation. AIDS 29, 1263–1265 (2015).

    CAS  PubMed  Google Scholar 

  312. Rogers, M. L., Schultz, D. W., Karnaros, V. & Shepheard, S. R. Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations. Brain Commun. 5, fcad287 (2023).

    PubMed  PubMed Central  Google Scholar 

  313. Bogdanov, M. et al. Increased oxidative damage to DNA in ALS patients. Free Radic. Biol. Med. 29, 652–658 (2000).

    CAS  PubMed  Google Scholar 

  314. Saitoh, Y. & Takahashi, Y. Riluzole for the treatment of amyotrophic lateral sclerosis. Neurodegener. Dis. Manag. 10, 343–355 (2020).

    PubMed  Google Scholar 

  315. Huang, C. S., Song, J. H., Nagata, K., Yeh, J. Z. & Narahashi, T. Effects of the neuroprotective agent riluzole on the high voltage-activated calcium channels of rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 282, 1280–1290 (1997).

    CAS  PubMed  Google Scholar 

  316. Fang, T. et al. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 17, 416–422 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  317. Chen, L., Liu, X., Tang, L., Zhang, N. & Fan, D. Long-term use of riluzole could improve the prognosis of sporadic amyotrophic lateral sclerosis patients: a real-world cohort study in China. Front. Aging Neurosci. 8, 246 (2016).

    PubMed  PubMed Central  Google Scholar 

  318. Sanderink, G. J., Bournique, B., Stevens, J., Petry, M. & Martinet, M. Involvement of human CYP1A isoenzymes in the metabolism and drug interactions of riluzole in vitro. J. Pharmacol. Exp. Ther. 282, 1465–1472 (1997).

    CAS  PubMed  Google Scholar 

  319. Ou‐Yang, D. et al. Phenotypic polymorphism and gender‐related differences of CYP1A2 activity in a Chinese population. Br. J. Clin. Pharmacol. 49, 145–151 (2000).

    PubMed  PubMed Central  Google Scholar 

  320. Guengerich, F. P. & Shimada, T. Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem. Res. Toxicol. 4, 391–407 (1991).

    CAS  PubMed  Google Scholar 

  321. Armon, C. Smoking may be considered an established risk factor for sporadic ALS. Neurology 73, 1693–1698 (2009).

    PubMed  PubMed Central  Google Scholar 

  322. Higgins, S. T. et al. A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004–2014. Prev. Med. 80, 89–100 (2015).

    PubMed  PubMed Central  Google Scholar 

  323. Bruno, R. et al. Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis. Clin. Pharmacol. Ther. 62, 518–526 (1997).

    CAS  PubMed  Google Scholar 

  324. Miller, T. M. et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 387, 1099–1110 (2022).

    CAS  PubMed  Google Scholar 

  325. Steinacker, P. et al. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J. Neurol. Neurosurg. Psychiatry 87, 12–20 (2016).

    PubMed  Google Scholar 

  326. Thompson, A. G. et al. Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain. Brain Commun. 4, fcac029 (2022).

    PubMed  PubMed Central  Google Scholar 

  327. Benatar, M. et al. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology 95, e59–e69 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  328. Abu-Rumeileh, S. et al. Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis. J. Neurol. 267, 1699–1708 (2020).

    CAS  PubMed  Google Scholar 

  329. De Schaepdryver, M. et al. Neurofilament light chain and C reactive protein explored as predictors of survival in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 91, 436–437 (2020).

    PubMed  Google Scholar 

  330. Lu, C. H. et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology 84, 2247–2257 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  331. Verde, F. et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 90, 157–164 (2019).

    PubMed  Google Scholar 

  332. Poesen, K. & Van Damme, P. Diagnostic and prognostic performance of neurofilaments in ALS. Front. Neurol. 9, 1167 (2019).

    PubMed  PubMed Central  Google Scholar 

  333. Bali, T. et al. Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J. Neurol. Neurosurg. Psychiatry 88, 99–105 (2017).

    PubMed  Google Scholar 

  334. Shobeiri, P., Kalantari, A., Teixeira, A. L. & Rezaei, N. Shedding light on biological sex differences and microbiota-gut-brain axis: a comprehensive review of its roles in neuropsychiatric disorders. Biol. Sex Differ. 13, 12 (2022).

    PubMed  PubMed Central  Google Scholar 

  335. Stachenfeld, N. S. & Mazure, C. M. Precision medicine requires understanding how both sex and gender influence health. Cell 185, 1619–1622 (2022).

    CAS  PubMed  Google Scholar 

  336. Bohr, T. et al. The glymphatic system: current understanding and modeling. iScience 25, 104987 (2022).

    PubMed  PubMed Central  Google Scholar 

  337. Hablitz, L. M. & Nedergaard, M. The glymphatic system: a novel component of fundamental neurobiology. J. Neurosci. 41, 7698–7711 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  338. Yuan, A. & Nixon, R. A. Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies. Front. Neurosci. 15, 689938 (2021).

    PubMed  PubMed Central  Google Scholar 

  339. Beckman, K. B. & Ames, B. N. Oxidative decay of DNA. J. Biol. Chem. 272, 19633–19636 (1997).

    CAS  PubMed  Google Scholar 

  340. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    CAS  PubMed  Google Scholar 

  341. Lambrechts, D. & Carmeliet, P. VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim. Biophys. Acta Mol. Basis Dis. 1762, 1109–1121 (2006).

    CAS  Google Scholar 

  342. Lambrechts, D. et al. Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype. J. Med. Genet. 46, 840–846 (2009).

    CAS  PubMed  Google Scholar 

  343. Ohta, Y. et al. Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis. J. Neurosci. Res. 97, 607–619 (2019).

    CAS  PubMed  Google Scholar 

  344. Canadian Agency for Drugs and Technologies in Health. Sodium Phenylbutyrate and Ursodoxicoltaurine (Albrioza) (CADTH, 2022).

Download references

Acknowledgements

The authors are grateful to M. Bankole for the early discussions about this topic, and to B. Belanger for designing the original figures. Original work in the laboratories of the authors is supported by grants from the Canadian Institutes of Health Research (CIHR, to K.A.S. (FRN148380) and M.D.N. (FRN159591)), the K-Brain Project of the National Research Foundation (NRF, to S.H.K. (RS-2023-00265515)), the Krembil Foundation (to M.D.N.), the CIHR/International Development Research Centre (CIHR/IDRC 109927 to G.P.), the ALS Society of Canada (to M.D.N. and G.P.), the Barry Barrett Foundation (to M.D.N. and G.P.) and the Rose Family Foundation (to M.D.N. and G.P.). S.S.L. was a recipient of an Alberta Graduate Excellence Scholarship, a CIHR Master’s Scholarship, a Faculty of Graduate Studies Master’s Research Scholarship from the University of Calgary, and a Donald Burns and Louise Berlin Graduate Award in Dementia from the Hotchkiss Brain Institute. S.M.J. was a recipient of an Alberta Graduate Excellence Scholarship and Spinal Cord, Nerve Injury & Pain Scholarship from the University of Calgary Hotchkiss Brain Institute.

Author information

Authors and Affiliations

  1. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Sarah M. Jacob, Sukyoung Lee, Keith A. Sharkey, Gerald Pfeffer & Minh Dang Nguyen

  2. Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Sarah M. Jacob, Sukyoung Lee, Gerald Pfeffer & Minh Dang Nguyen

  3. Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Sukyoung Lee & Minh Dang Nguyen

  4. Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Sukyoung Lee & Minh Dang Nguyen

  5. Department of Neurology, Hanyang University Hospital, Seoul, South Korea

    Seung Hyun Kim

  6. Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Keith A. Sharkey

  7. Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Keith A. Sharkey

  8. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Gerald Pfeffer

Authors
  1. Sarah M. Jacob
    View author publications

    Search author on:PubMed Google Scholar

  2. Sukyoung Lee
    View author publications

    Search author on:PubMed Google Scholar

  3. Seung Hyun Kim
    View author publications

    Search author on:PubMed Google Scholar

  4. Keith A. Sharkey
    View author publications

    Search author on:PubMed Google Scholar

  5. Gerald Pfeffer
    View author publications

    Search author on:PubMed Google Scholar

  6. Minh Dang Nguyen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

S.M.J., S.S.L., G.P., S.H.K., K.A.S. and M.D.N. wrote the manuscript. All authors critically reviewed the manuscript drafts and approved the final manuscript for submission.

Corresponding authors

Correspondence to Gerald Pfeffer or Minh Dang Nguyen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks Pamela McCombe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jacob, S.M., Lee, S., Kim, S.H. et al. Brain–body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis. Nat Rev Neurol 20, 475–494 (2024). https://doi.org/10.1038/s41582-024-00991-7

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41582-024-00991-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing