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Review
. 2025 Feb;31(2):396-408.
doi: 10.1038/s41591-024-03469-7. Epub 2025 Jan 30.

Toward a biological definition of neuronal and glial synucleinopathies

Affiliations
Review

Toward a biological definition of neuronal and glial synucleinopathies

Claudio Soto et al. Nat Med. 2025 Feb.

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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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

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