Toward a biological definition of neuronal and glial synucleinopathies
- PMID: 39885358
- DOI: 10.1038/s41591-024-03469-7
Toward a biological definition of neuronal and glial synucleinopathies
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.
© 2025. Springer Nature America, Inc.
Conflict of interest statement
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.
References
-
- Bras, I. C. et al. Synucleinopathies: where we are and where we need to go. J. Neurochem. 153, 433–454 (2020). - PubMed
-
- Goedert, M., Jakes, R. & Spillantini, M. G. The synucleinopathies: twenty years on. J. Parkinsons Dis. 7, S53–S71 (2017).
-
- Poewe, W. et al. Diagnosis and management of Parkinson’s disease dementia. Int. J. Clin. Pract. 62, 1581–1587 (2008). - PubMed
-
- Rocca, W. A. The future burden of Parkinson’s disease. Mov. Disord. 33, 8–9 (2018). - PubMed
-
- Desai, U. et al. Epidemiology and economic burden of Lewy body dementia in the United States. Curr. Med. Res. Opin. 38, 1177–1188 (2022). - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- ZEN24-1069572, SG-23-1061717/ALZ/Alzheimer's Association/United States
- U01 NS100610/NS/NINDS NIH HHS/United States
- R01NS131658, U01NS113851 and U01NS122419/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
- NS115114/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
- U01NS100610/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
LinkOut - more resources
Full Text Sources
Medical