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.

  • Article
  • Published:

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain

Molecular Psychiatry volume 30, pages 3039–3054 (2025)Cite this article

Subjects

Abstract

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson’s disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no difference in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th+/Vglut2+ neurons, Th and Vglut2 transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (e.g., terminals and axonal projections) did not differ throughout aging. Similar to the mouse, an initial study of human brain showed no effect of aging on midbrain neuron number with a concomitant decrease in TH and VGLUT2 mRNA expression. Unlike in mice, the density of striatal TH+ dopaminergic terminals was lower in aged human subjects. However, TH and VGLUT2 protein levels were unaffected in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th+ neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Age-related decreases in Th mRNA expression in mouse VTA and SNc.
Fig. 2: Th and Vglut2 mRNA expression decrease across aging in distinct midbrain neuron subpopulations.
Fig. 3: Th and Vglut2 protein expression is unaltered across aging in mouse striatum.
Fig. 4: Age-related decreases in TH and VGLUT2 mRNA expression in human VTA and SNc.
Fig. 5: TH and VGLUT2 protein expression in projections to human striatum remain unchanged throughout aging.
Fig. 6: Rpl6 mRNA expression is preserved across aging in the mouse midbrain.

Similar content being viewed by others

Data availability

Transcriptomic analyses employed previously deposited RNA sequencing data (GSE129788). Customized computer code has been deposited in Github and can be accessed at: https://github.com/tsbanks16/Aging_Paper.

References

  1. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord. 2013;28:715–24.

    PubMed  Google Scholar 

  2. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev. 2014;14:19–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee J, Kim HJ. Normal aging induces changes in the brain and neurodegeneration progress: review of the structural, biochemical, metabolic, cellular, and molecular changes. Front Aging Neurosci. 2022;14:931536.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ota M, Yasuno F, Ito H, Seki C, Nozaki S, Asada T, et al. Age-related decline of dopamine synthesis in the living human brain measured by positron emission tomography with L-[beta-11C]DOPA. Life Sci. 2006;79:730–6.

    CAS  PubMed  Google Scholar 

  5. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley SJ, et al. Dopamine transporters decrease with age. J Nucl Med. 1996;37:554–9.

    CAS  PubMed  Google Scholar 

  6. Kaasinen V, Vilkman H, Hietala J, Någren K, Helenius H, Olsson H, et al. Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain. Neurobiol Aging. 2000;21:683–8.

    CAS  PubMed  Google Scholar 

  7. Coleman CR, Pallos J, Arreola-Bustos A, Wang L, Raftery D, Promislow DEL, et al. Natural variation in age-related dopamine neuron degeneration is glutathione-dependent and linked to life span. bioRxiv. 2024; https://doi.org/10.1101/2024.02.12.580013.

  8. Noda S, Sato S, Fukuda T, Tada N, Hattori N. Aging-related motor function and dopaminergic neuronal loss in C57BL/6 mice. Mol Brain. 2020;13:46.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lebowitz JJ, Khoshbouei H. Heterogeneity of dopamine release sites in health and degeneration. Neurobiol Dis. 2020;134:104633.

    CAS  PubMed  Google Scholar 

  10. Dickerson JW, Hemmerle AM, Numan S, Lundgren KH, Seroogy KB. Decreased expression of ErbB4 and tyrosine hydroxylase mRNA and protein in the ventral midbrain of aged rats. Neuroscience. 2009;163:482–9.

    CAS  PubMed  Google Scholar 

  11. Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, et al. Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol. 1998;401:253–65.

    CAS  PubMed  Google Scholar 

  12. Siddiqi Z, Kemper TL, Killiany R. Age-related neuronal loss from the substantia nigra-pars compacta and ventral tegmental area of the rhesus monkey. J Neuropathol Exp Neurol. 1999;58:959–71.

    CAS  PubMed  Google Scholar 

  13. Bannon MJ, Poosch MS, Xia Y, Goebel DJ, Cassin B, Kapatos G. Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age. Proc Natl Acad Sci. 1992;89:7095–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bannon MJ, Whitty CJ. Age-related and regional differences in dopamine transporter mRNA expression in human midbrain. Neurology. 1997;48:969–77.

    CAS  PubMed  Google Scholar 

  15. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991;114:2283–301.

    PubMed  Google Scholar 

  16. Gibb WR, Lees AJ. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1991;54:388–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ma SY, Roytt M, Collan Y, Rinne JO. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol. 1999;25:394–9.

    CAS  PubMed  Google Scholar 

  18. Muthane U, Yasha TC, Shankar SK. Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India. Ann Neurol. 1998;43:283–7.

    CAS  PubMed  Google Scholar 

  19. Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, et al. Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain. 2000;123:366–73.

    PubMed  Google Scholar 

  20. Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B. Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol. 2002;28:283–91.

    CAS  PubMed  Google Scholar 

  21. Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH. Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol. 2002;450:203–14.

    CAS  PubMed  Google Scholar 

  22. Pakkenberg B, Møller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry. 1991;54:30–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lin KJ, Weng YH, Hsieh CJ, Lin WY, Wey SP, Kung MP, et al. Brain imaging of vesicular monoamine transporter type 2 in healthy aging subjects by 18F-FP-(+)-DTBZ PET. PLoS ONE. 2013;8:e75952.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hall FS, Itokawa K, Schmitt A, Moessner R, Sora I, Lesch KP, et al. Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems. Neuropharmacology. 2014;76:146–55.

    CAS  PubMed  Google Scholar 

  25. Sun Y, Li YS, Li B, Ma K, Li BX. A study of the age-related effects of lactational atrazine exposure. Reprod Toxicol. 2017;69:230–41.

    CAS  PubMed  Google Scholar 

  26. Buccitelli C, Selbach M. mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 2020;21:630–44.

    CAS  PubMed  Google Scholar 

  27. Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13:227–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Buck SA, Steinkellner T, Aslanoglou D, Villeneuve M, Bhatte SH, Childers VC, et al. Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age-related neurodegeneration. Aging Cell. 2021;20:e13365.

  29. Flurkey K, Currer J, Harrison D. Mouse models in aging research. The Mouse in Biomedical Res. 2007;3:637–72.

  30. Buck SA, Miranda BR, Logan RW, Fish KN, Greenamyre JT, Freyberg Z. VGLUT2 is a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration. J Neurosci. 2021;41:4937–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. J Gene Med. 2010;12:561–3.

    PubMed  Google Scholar 

  32. Drummond GB, Paterson DJ, McGrath JC. ARRIVE: new guidelines for reporting animal research. Exp Physiol. 2010;95:841.

    PubMed  Google Scholar 

  33. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412.

    PubMed  PubMed Central  Google Scholar 

  34. Kelly TM, Mann JJ. Validity of DSM-III-R diagnosis by psychological autopsy: a comparison with clinician ante-mortem diagnosis. Acta Psychiatr Scand. 1996;94:337–43.

    CAS  PubMed  Google Scholar 

  35. Lewis DA. The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology. 2002;26:143–54.

    PubMed  Google Scholar 

  36. Deep-Soboslay A, Akil M, Martin CE, Bigelow LB, Herman MM, Hyde TM, et al. Reliability of psychiatric diagnosis in postmortem research. Biol Psychiatry. 2005;57:96–101.

    PubMed  Google Scholar 

  37. Glausier JR, Kelly MA, Salem S, Chen K, Lewis DA. Proxy measures of premortem cognitive aptitude in postmortem subjects with schizophrenia. Psychol Med. 2020;50:507–14.

    PubMed  Google Scholar 

  38. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57:65–73.

    CAS  PubMed  Google Scholar 

  39. Motulsky HJ, Brown RE. Detecting outliers when fitting data with nonlinear regression - a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinforma. 2006;7:123.

    Google Scholar 

  40. Paxinos G, Franklin KBJ The Mouse Brain in Stereotaxic Coordinates. San Diego: Academic Press; 2001.

  41. Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN, et al. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry. 2011;168:921–9.

    PubMed  PubMed Central  Google Scholar 

  42. Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry. 2014;19:30–36.

    CAS  PubMed  Google Scholar 

  43. Rocco BR, Lewis DA, Fish KN. Markedly lower glutamic acid decarboxylase 67 protein levels in a subset of boutons in schizophrenia. Biol Psychiatry. 2016;79:1006–15.

    CAS  PubMed  Google Scholar 

  44. Rocco BR, Sweet RA, Lewis DA, Fish KN. GABA-synthesizing enzymes in calbindin and calretinin neurons in monkey prefrontal cortex. Cereb Cortex. 2016;26:2191–204.

    PubMed  Google Scholar 

  45. Zhang S, Qi J, Li X, Wang HL, Britt JP, Hoffman AF, et al. Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons. Nat Neurosci. 2015;18:386–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Herzog E, Takamori S, Jahn R, Brose N, Wojcik SM. Synaptic and vesicular co-localization of the glutamate transporters VGLUT1 and VGLUT2 in the mouse hippocampus. J Neurochem. 2006;99:1011–8.

    CAS  PubMed  Google Scholar 

  47. Chen SY, Lu KM, Ko HA, Huang TH, Hao JH, Yan YT, et al. Parcellation of the striatal complex into dorsal and ventral districts. Proc Natl Acad Sci. 2020;117:7418–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Fish KN, Sweet RA, Deo AJ, Lewis DA. An automated segmentation methodology for quantifying immunoreactive puncta number and fluorescence intensity in tissue sections. Brain Res. 2008;1240:62–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ximerakis M, Lipnick SL, Innes BT, Simmons SK, Adiconis X, Dionne D, et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat Neurosci. 2019;22:1696–708.

    CAS  PubMed  Google Scholar 

  50. Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer International Publishing; 2009.

  51. Poulin JF, Caronia G, Hofer C, Cui Q, Helm B, Ramakrishnan C, et al. Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches. Nat Neurosci. 2018;21:1260–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Trudeau LE, Hnasko TS, Wallen-Mackenzie A, Morales M, Rayport S, Sulzer D. The multilingual nature of dopamine neurons. Prog Brain Res. 2014;211:141–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Morales M, Margolis EB. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat Rev Neurosci. 2017;18:73–85.

    CAS  PubMed  Google Scholar 

  54. Buck SA, Erickson-Oberg MQ, Bhatte SH, McKellar CD, Ramanathan VP, Rubin SA, et al. Roles of VGLUT2 and dopamine/glutamate Co-transmission in selective vulnerability to dopamine neurodegeneration. ACS Chem Neurosci. 2022;13:187–93.

    CAS  PubMed  Google Scholar 

  55. Mingote S, Amsellem A, Kempf A, Rayport S, Chuhma N. Dopamine-glutamate neuron projections to the nucleus accumbens medial shell and behavioral switching. Neurochemistry Int. 2019;129:104482.

    CAS  Google Scholar 

  56. Mingote S, Chuhma N, Kusnoor SV, Field B, Deutch AY, Rayport S. Functional connectome analysis of dopamine neuron glutamatergic connections in forebrain regions. J Neurosci. 2015;35:16259–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chuhma N, Choi WY, Mingote S, Rayport S. Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection. Neuroscience. 2009;164:1068–83.

    CAS  PubMed  Google Scholar 

  58. Stuber GD, Hnasko TS, Britt JP, Edwards RH, Bonci A. Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci. 2010;30:8229–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Tecuapetla F, Patel JC, Xenias H, English D, Tadros I, Shah F, et al. Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens. J Neurosci. 2010;30:7105–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Fortin GM, Ducrot C, Giguere N, Kouwenhoven WM, Bourque MJ, Pacelli C, et al. Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells. FASEB J. 2019;33:400–17.

    CAS  PubMed  Google Scholar 

  61. Silm K, Yang J, Marcott PF, Asensio CS, Eriksen J, Guthrie DA, et al. Synaptic vesicle recycling pathway determines neurotransmitter content and release properties. Neuron. 2019;102:786–800.e785.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gulati M, Jain N, Davis JH, Williamson JR, Britton RA. Functional interaction between ribosomal protein L6 and RbgA during ribosome assembly. PLoS Genet. 2014;10:e1004694.

    PubMed  PubMed Central  Google Scholar 

  63. Yang C, Zang W, Ji Y, Li T, Yang Y, Zheng X. Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase-dependent manner and regulates the DNA damage response. J Biol Chem. 2019;294:2827–38.

    CAS  PubMed  Google Scholar 

  64. Wolf ME, LeWitt PA, Bannon MJ, Dragovic LJ, Kapatos G. Effect of aging on tyrosine hydroxylase protein content and the relative number of dopamine nerve terminals in human caudate. J Neurochem. 1991;56:1191–1200.

    CAS  PubMed  Google Scholar 

  65. Srivastava P, Nishiyama S, Zhou F, Lin SH, Srivastava A, Su C, et al. Peripheral MC1R activation modulates immune responses and is neuroprotective in a mouse model of Parkinson’s disease. J Neuroimmune Pharmacol. 2023;18:704–17.

    PubMed  PubMed Central  Google Scholar 

  66. Cai W, Srivastava P, Feng D, Lin Y, Vanderburg CR, Xu Y, et al. Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson’s disease. Mol Neurodegener. 2022;17:16.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Di Lorenzo Alho AT, Suemoto CK, Polichiso L, Tampellini E, de Oliveira KC, Molina M, et al. Three-dimensional and stereological characterization of the human substantia nigra during aging. Brain Struct Funct. 2016;221:3393–403.

    PubMed  Google Scholar 

  68. Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B. A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res. 1995;693:201–6.

    CAS  PubMed  Google Scholar 

  69. Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience. 1995;67:631–47.

    CAS  PubMed  Google Scholar 

  70. Meissner W, Prunier C, Guilloteau D, Chalon S, Gross CE, Bezard E. Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Mol Neurobiol. 2003;28:209–18.

    CAS  PubMed  Google Scholar 

  71. Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, et al. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci. 2001;21:6853–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Seniuk NA, Tatton WG, Greenwood CE. Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP. Brain Res. 1990;527:7–20.

    CAS  PubMed  Google Scholar 

  73. Sukoff Rizzo SJ, Anderson LC, Green TL, McGarr T, Wells G, Winter SS. Assessing healthspan and lifespan measures in aging mice: optimization of testing protocols, replicability, and rater reliability. Curr Protoc Mouse Biol. 2018;8:e45.

    PubMed  Google Scholar 

  74. Dovonou A, Bolduc C, Soto Linan V, Gora C, Peralta Iii MR, Lévesque M. Animal models of Parkinson’s disease: bridging the gap between disease hallmarks and research questions. Transl Neurodegener. 2023;12:36.

    PubMed  PubMed Central  Google Scholar 

  75. Wolfarth S, Konieczny J, Smiałowska M, Schulze G, Ossowska K. Influence of 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway on the muscle tone and electromyographic activity measured during passive movements. Neuroscience. 1996;74:985–96.

    CAS  PubMed  Google Scholar 

  76. Olsson M, Nikkhah G, Bentlage C, Björklund A. Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci. 1995;15:3863–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Fleming SM, Zhu C, Fernagut PO, Mehta A, DiCarlo CD, Seaman RL, et al. Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp Neurol. 2004;187:418–29.

    CAS  PubMed  Google Scholar 

  78. Guimarães RP, Resende MCS, Tavares MM, Belardinelli de Azevedo C, Ruiz MCM, Mortari MR. Construct, face, and predictive validity of Parkinson’s disease rodent models. Int J Mol Sci. 2024;25:8971.

    PubMed  PubMed Central  Google Scholar 

  79. Segovia G, Porras A, Del Arco A, Mora F. Glutamatergic neurotransmission in aging: a critical perspective. Mech Ageing Dev. 2001;122:1–29.

    CAS  PubMed  Google Scholar 

  80. Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR. Changes in the structural complexity of the aged brain. Aging Cell. 2007;6:275–84.

    CAS  PubMed  Google Scholar 

  81. Donzanti BA, Ung AK. Alterations in neurotransmitter amino acid content in the aging rat striatum are subregion dependent. Neurobiol Aging. 1990;11:159–62.

    CAS  PubMed  Google Scholar 

  82. Benedetti MS, Russo A, Marrari P, Dostert P. Effects of ageing on the content in sulfur-containing amino acids in rat brain. J Neural Transm Gen Sect. 1991;86:191–203.

    CAS  PubMed  Google Scholar 

  83. Corsi C, Melani A, Bianchi L, Pepeu G, Pedata F. Striatal A2A adenosine receptors differentially regulate spontaneous and K+-evoked glutamate release in vivo in young and aged rats. Neuroreport. 1999;10:687–91.

    CAS  PubMed  Google Scholar 

  84. Segovia G, Del Arco A, Mora F. Effects of aging on the interaction between glutamate, dopamine, and GABA in striatum and nucleus accumbens of the awake rat. J Neurochem. 1999;73:2063–72.

    CAS  PubMed  Google Scholar 

  85. Trudeau LE, El Mestikawy S. Glutamate cotransmission in cholinergic, GABAergic and monoamine systems: contrasts and commonalities. Front Neural Circuits. 2018;12:113.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Trudeau LE, Gutierrez R. On cotransmission & neurotransmitter phenotype plasticity. Mol Interv. 2007;7:138–46.

    CAS  PubMed  Google Scholar 

  87. Hnasko TS, Edwards RH. Neurotransmitter corelease: mechanism and physiological role. Annu Rev Physiol. 2012;74:225–43.

    CAS  PubMed  Google Scholar 

  88. Aguilar JI, Dunn M, Mingote S, Karam CS, Farino ZJ, Sonders MS, et al. Neuronal depolarization drives increased dopamine synaptic vesicle loading via VGLUT. Neuron. 2017;95:1074–1088.e1077.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, et al. Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron. 2010;65:643–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Buck SA, Rubin SA, Kunkhyen T, Treiber CD, Xue X, Fenno LE, et al. Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration. bioRxiv. 2023; https://doi.org/10.1101/2023.10.02.560584.

  91. Kumar A, Thirumurugan K. Understanding cellular senescence: pathways involved, therapeutics and longevity aiding. Cell Cycle. 2023;22:1–22.

  92. Shen R, Ardianto C, Celia C, Sidharta VM, Sasmita PK, Satriotomo I, et al. Brain-derived neurotrophic factor interplay with oxidative stress: neuropathology approach in potential biomarker of Alzheimer’s disease. Dement Neuropsychol. 2023;17:e20230012.

    PubMed  PubMed Central  Google Scholar 

  93. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2014;507:448–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Meiser J, Weindl D, Hiller K. Complexity of dopamine metabolism. Cell Commun Signal: CCS. 2013;11:34.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Van Laar VS, Chen J, Zharikov AD, Bai Q, Di Maio R, Dukes AA, et al. α-Synuclein amplifies cytoplasmic peroxide flux and oxidative stress provoked by mitochondrial inhibitors in CNS dopaminergic neurons in vivo. Redox Biol. 2020;37:101695.

    PubMed  PubMed Central  Google Scholar 

  96. Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023;186:305–326.e327.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Anirudhan A, Angulo-Bejarano PI, Paramasivam P, Manokaran K, Kamath SM, Murugesan R, et al. RPL6: a key molecule regulating zinc- and magnesium-bound metalloproteins of Parkinson’s disease. Front Neurosci. 2021;15:631892.

    PubMed  PubMed Central  Google Scholar 

  98. Dracheva S, Elhakem SL, McGurk SR, Davis KL, Haroutunian V. GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. J Neurosci Res. 2004;76:581–92.

    CAS  PubMed  Google Scholar 

  99. Di Maio A, De Rosa A, Pelucchi S, Garofalo M, Marciano B, Nuzzo T, et al. Analysis of mRNA and protein levels of CAP2, DLG1 and ADAM10 genes in post-mortem brain of schizophrenia, Parkinson’s and Alzheimer’s disease patients. Int J Mol Sci. 2022;23:1539.

    PubMed  PubMed Central  Google Scholar 

  100. Glausier JR, Lewis DA. Selective pyramidal cell reduction of GABA(A) receptor α1 subunit messenger RNA expression in schizophrenia. Neuropsychopharmacology. 2011;36:2103–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Zahn JM, Sonu R, Vogel H, Crane E, Mazan-Mamczarz K, Rabkin R, et al. Transcriptional profiling of aging in human muscle reveals a common aging signature. PLoS Genet. 2006;2:e115.

    PubMed  PubMed Central  Google Scholar 

  102. Davie K, Janssens J, Koldere D, De Waegeneer M, Pech U, Kreft Ł, et al. A single-cell transcriptome atlas of the aging drosophila brain. Cell. 2018;174:982–998.e920.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Parry TJ, Theisen JW, Hsu JY, Wang YL, Corcoran DL, Eustice M, et al. The TCT motif, a key component of an RNA polymerase II transcription system for the translational machinery. Genes Dev. 2010;24:2013–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Liu-Yesucevitz L, Bassell GJ, Gitler AD, Hart AC, Klann E, Richter JD, et al. Local RNA translation at the synapse and in disease. J Neurosci. 2011;31:16086–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang DO, Kim SM, Zhao Y, Hwang H, Miura SK, Sossin WS, et al. Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science. 2009;324:1536–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Heo S, Diering GH, Na CH, Nirujogi RS, Bachman JL, Pandey A, et al. Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. Proc Natl Acad Sci. 2018;115:E3827–e3836.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Calderwood SK, Murshid A, Prince T. The shock of aging: molecular chaperones and the heat shock response in longevity and aging-a mini-review. Gerontology. 2009;55:550–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. David DC. Aging and the aggregating proteome. Front Genet. 2012;3:247.

    PubMed  PubMed Central  Google Scholar 

  109. Kaushik S, Cuervo AM. Proteostasis and aging. Nat Med. 2015;21:1406–15.

    CAS  PubMed  Google Scholar 

  110. Labbadia J, Morimoto RI. Proteostasis and longevity: when does aging really begin? F1000Prime Rep. 2014;6:7.

    PubMed  PubMed Central  Google Scholar 

  111. Soti C, Csermely P. Aging and molecular chaperones. Exp Gerontol. 2003;38:1037–40.

    CAS  PubMed  Google Scholar 

  112. Alegre-Abarrategui J, Brimblecombe KR, Roberts RF, Velentza-Almpani E, Tilley BS, Bengoa-Vergniory N, et al. Selective vulnerability in α-synucleinopathies. Acta Neuropathol. 2019;138:681–704.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful for discussions and technical assistance provided by Drs. Emma O’Leary, Tyler Fortuna, Eric Zimmerman, Stacey Sukoff Rizzo, and George Tseng. We thank Dr. Hriday Bhambhvani for statistical consultation and Hung-Ching (Rick) Chang for assistance with code deposition. Postmortem human brain tissue was provided by the NIH NeuroBioBank and the University of Pittsburgh Brain and Tissue Donation Program. This study was supported by The Pittsburgh Foundation (John F and Nancy A Emmerling Fund of the Pittsburgh Foundation, FPG00043 to ZF), the Commonwealth of Pennsylvania (PA-HEALTH to ZF), and the National Institutes of Health (R21AG068607 to ZF; R21AA028800 to ZF and RWL; R01ES034037 to ZF; 3R01ES034037-02A1 Supplement to ZF; R01DK124219 to ZF; R01DA061243 to ZF and RWL; F31NS11811 to SAB; R36DA057972 to JK; T32MH019986 to SJM; T32GM133353 to CW and JK).

Author information

Author notes

  1. These authors contributed equally: Silas A. Buck, Samuel J. Mabry.

Authors and Affiliations

  1. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Silas A. Buck & Jenesis Kozel

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Silas A. Buck, Samuel J. Mabry, Jill R. Glausier, Tabitha Banks-Tibbs, Caroline Ward, Jenesis Kozel, Kenneth N. Fish, David A. Lewis & Zachary Freyberg

  3. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    Tabitha Banks-Tibbs & Caroline Ward

  4. College of Medicine, The Ohio State University, Columbus, OH, USA

    Tabitha Banks-Tibbs

  5. Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Chen Fu & Ryan W. Logan

  6. Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Ryan W. Logan

  7. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Zachary Freyberg

Authors
  1. Silas A. Buck
    View author publications

    Search author on:PubMed Google Scholar

  2. Samuel J. Mabry
    View author publications

    Search author on:PubMed Google Scholar

  3. Jill R. Glausier
    View author publications

    Search author on:PubMed Google Scholar

  4. Tabitha Banks-Tibbs
    View author publications

    Search author on:PubMed Google Scholar

  5. Caroline Ward
    View author publications

    Search author on:PubMed Google Scholar

  6. Jenesis Kozel
    View author publications

    Search author on:PubMed Google Scholar

  7. Chen Fu
    View author publications

    Search author on:PubMed Google Scholar

  8. Kenneth N. Fish
    View author publications

    Search author on:PubMed Google Scholar

  9. David A. Lewis
    View author publications

    Search author on:PubMed Google Scholar

  10. Ryan W. Logan
    View author publications

    Search author on:PubMed Google Scholar

  11. Zachary Freyberg
    View author publications

    Search author on:PubMed Google Scholar

Contributions

SAB and ZF conceived the project. SAB, SJM, JRG, CW, TBT, JK, KNF, and RWL performed imaging experiments and data analysis. JRG and DAL prepared postmortem human brain samples. CF and RWL performed the transcriptomic analyses. SAB, SJM, JK, and ZF wrote the manuscript with contributions from co-authors.

Corresponding author

Correspondence to Zachary Freyberg.

Ethics declarations

Competing interests

ZF is funded by an investigator-initiated award from UPMC Enterprises, which is unrelated to the present study.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. For all research concerning human subjects, informed consent for donation was obtained from the decedent’s next-of-kin. All procedures were approved by the University of Pittsburgh’s Committee for the Oversight of Research and Clinical Training Involving Decedents and Institutional Review Board for Biomedical Research. None of the images in the current work are identifiable from human research participants.

Additional information

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

Supplementary information

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

Buck, S.A., Mabry, S.J., Glausier, J.R. et al. Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain. Mol Psychiatry 30, 3039–3054 (2025). https://doi.org/10.1038/s41380-025-02909-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-025-02909-1

This article is cited by

Search

Advanced search

Quick links