Toward a biological definition of neuronal and glial synucleinopathies

Claudio Soto¹, Brit Mollenhauer^{2

3

4

5}, Oskar Hansson^{6

7}, Un Jung Kang⁸, Roy N Alcalay^{9

10}, David Standaert¹¹, Claudia Trenkwalder^{2

3}, Kenneth Marek¹², Douglas Galasko¹³, Kathleen Poston¹⁴

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. Soto@uth.tmc.edu.
² University Medical Center Göttingen, Department of Neurology, Göttingen, Germany.
³ Paracelsus-Elena-Klinik, Kassel, Germany.
⁴ Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.
⁵ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁶ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
⁷ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
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.
⁹ Columbia University Irving Medical Center, New York, NY, USA.
¹⁰ Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine, Tel Aviv, Israel.
¹¹ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
¹² Institute for Neurodegerative Disorders, New Haven, CT, USA.
¹³ Department of Neurosciences and Shiley-Marcos Alzheimer's Disease Research Center, UC San Diego, La Jolla, CA, USA.
¹⁴ Department of Neurology & Neurological Sciences, Stanford Movement Disorders Center, Stanford University, Stanford, CA, USA.

PMID: 39885358
DOI: 10.1038/s41591-024-03469-7

Review

Toward a biological definition of neuronal and glial synucleinopathies

Claudio Soto et al. Nat Med. 2025 Feb.

. 2025 Feb;31(2):396-408.

doi: 10.1038/s41591-024-03469-7. Epub 2025 Jan 30.

Authors

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. Soto@uth.tmc.edu.
² University Medical Center Göttingen, Department of Neurology, Göttingen, Germany.
³ Paracelsus-Elena-Klinik, Kassel, Germany.
⁴ Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.
⁵ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁶ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.
⁷ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
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.
⁹ Columbia University Irving Medical Center, New York, NY, USA.
¹⁰ Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine, Tel Aviv, Israel.
¹¹ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
¹² Institute for Neurodegerative Disorders, New Haven, CT, USA.
¹³ Department of Neurosciences and Shiley-Marcos Alzheimer's Disease Research Center, UC San Diego, La Jolla, CA, USA.
¹⁴ Department of Neurology & Neurological Sciences, Stanford Movement Disorders Center, Stanford University, Stanford, CA, USA.

PMID: 39885358
DOI: 10.1038/s41591-024-03469-7

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.

PubMed Disclaimer

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

1. Bras, I. C. et al. Synucleinopathies: where we are and where we need to go. J. Neurochem. 153, 433–454 (2020). - PubMed
1. Goedert, M., Jakes, R. & Spillantini, M. G. The synucleinopathies: twenty years on. J. Parkinsons Dis. 7, S53–S71 (2017).
1. Poewe, W. et al. Diagnosis and management of Parkinson’s disease dementia. Int. J. Clin. Pract. 62, 1581–1587 (2008). - PubMed
1. Rocca, W. A. The future burden of Parkinson’s disease. Mov. Disord. 33, 8–9 (2018). - PubMed
1. 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

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

U24 AG079685/AG/NIA NIH HHS/United States

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Toward a biological definition of neuronal and glial synucleinopathies

Affiliations

Toward a biological definition of neuronal and glial synucleinopathies

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding