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Toward a biological definition of neuronal and glial synucleinopathies

Nature Medicine volume 31, pages 396–408 (2025)Cite this article

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Abstract

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases—collectively called synucleinopathies—which include Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living patients and to differentiate between neuronal or glial αSyn pathology. We anticipate that a biological definition of synucleinopathies, if well-integrated with the current clinical classifications, will enable further understanding of the disease pathogenesis and contribute to the development of effective, disease-modifying therapies.

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Fig. 1: The putative pathobiological pathway of synucleinopathies.
Fig. 2: A biologically anchored definition of synucleinopathies.
Fig. 3: Definition of neuronal and glial synuclein disease.
Fig. 4: Unknown nature and origin of αSyn seeds in CSF.

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Acknowledgements

C.S. received funding from NIH grants R01AG055053, U24AG079685 and R01AG079685, as well as grants from the Michael J. Fox Foundation for Parkinson’s Research (MJFF). B.M. is a member of the executive steering committee of the Parkinson Progression Marker Initiative of the MJFF and has received research funding from MJFF and Aligning Science Across Parkinson’s disease (ASAP, CRN). O.H. is supported by the European Research Council (ADG-101096455), the Alzheimer’s Association (ZEN24-1069572, SG-23-1061717), the GHR Foundation, the Swedish Research Council (2022-00775), ERA PerMed (ERAPERMED2021-184), the Knut and Alice Wallenberg foundation (2022-0231), Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-980907), the Swedish Brain Foundation (FO2021-0293), the Parkinson Foundation of Sweden (1412/22), the Cure Alzheimer’s Fund, the Rönström Family Foundation, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation (2020-O000028), the Regionalt Forskningsstöd (2022-1259) and the Swedish federal government under the ALF agreement (2022-Projekt0080). U.J.K. is supported by NIH grants R01NS131658, U01NS113851 and U01NS122419, R01NS133742 and U01NS126406. R.N.A. received funding from the Parkinson’s Foundation, the NIH, the Department of Defense, the MJFF, and the Silverstein Foundation for GBA/PD. D.S. is funded by Abbvie, the American Parkinson Disease Association, the MJFF, The National Parkinson Foundation, the Alabama Department of Commerce, the Alabama Innovation Fund, Genentech, the Department of Defense, and NIH grant P50NS108675. D.G. is funded by NIH grants P30AG062429 and U01NS100610. K.P. is a member of the executive steering committee of the Parkinson’s Progression Marker Initiative of the MJFF and has received funding from the MJFF and NIH (NS115114).

Author information

Authors and Affiliations

  1. Department of Neurology, Mitchell Center for Alzheimer’s disease and related brain disorders, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA

    Claudio Soto

  2. University Medical Center Göttingen, Department of Neurology, Göttingen, Germany

    Brit Mollenhauer & Claudia Trenkwalder

  3. Paracelsus-Elena-Klinik, Kassel, Germany

    Brit Mollenhauer & Claudia Trenkwalder

  4. Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany

    Brit Mollenhauer

  5. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA

    Brit Mollenhauer

  6. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden

    Oskar Hansson

  7. Memory Clinic, Skåne University Hospital, Malmö, Sweden

    Oskar Hansson

  8. Departments of Neurology and Neuroscience & Physiology, Neuroscience Institute, Fresco Institute for Parkinson’s Disease and Movement Disorders, Parekh Center for Interdisciplinary Neurology, Grossman School of Medicine, New York University, New York, NY, USA

    Un Jung Kang

  9. Columbia University Irving Medical Center, New York, NY, USA

    Roy N. Alcalay

  10. Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine, Tel Aviv, Israel

    Roy N. Alcalay

  11. Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    David Standaert

  12. Institute for Neurodegerative Disorders, New Haven, CT, USA

    Kenneth Marek

  13. Department of Neurosciences and Shiley-Marcos Alzheimer’s Disease Research Center, UC San Diego, La Jolla, CA, USA

    Douglas Galasko

  14. Department of Neurology & Neurological Sciences, Stanford Movement Disorders Center, Stanford University, Stanford, CA, USA

    Kathleen Poston

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Corresponding author

Correspondence to Claudio Soto.

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Competing interests

C.S. is a founder, chief scientific officer, shareholder and member of the board of directors of Amprion, a biotechnology company that focuses on the commercial use of seed amplification assays for high-sensitivity detection of misfolded protein aggregates involved in various neurodegenerative diseases. The University of Texas Health Science Center has licensed patents to Amprion. B.M. is scientific advisor to Amprion and has received honoraria for consultancy and/or educational presentations from GE, Bial, Roche, Biogen and AbbVie. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare and Roche. In the past 2 years, he has received consultancy or speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. U.J.K. is on the scientific advisory board of Amprion and consults for UCB, NurrOn and HanAll. R.N.A. has received consulting fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Sanofi, Servier, Takeda and Vanqua Bio. D.S. is a consultant for or received honoraria from Abbvie, Alnylam Pharmaceutics, Appello, Biohaven Pharmaceuticals, BlueRock Therapeutics, Coave Therapeutics Curium Pharma, F. Hoffman-La Roche, Eli Lilly USA, Sanofi-Aventis and Theravance. K.M. declares support from his institution (Institute for Neurodegenerative Disorders) from the MJFF, and consultancies for Invicro, Xing Imaging, Ixico, the MJFF, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Sanofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs and Prothena. D.G. has served as a consultant for GE Healthcare, Eisai and Biogen. K.P. is a scientific advisor to Amprion and has served as a consultant for Curasen, Novartis, Biohaven and Neuron23.

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Soto, C., Mollenhauer, B., Hansson, O. et al. Toward a biological definition of neuronal and glial synucleinopathies. Nat Med 31, 396–408 (2025). https://doi.org/10.1038/s41591-024-03469-7

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