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  • Review Article
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α-Synuclein pathology as a target in neurodegenerative diseases

Nature Reviews Neurology volume 21, pages 32–47 (2025)Cite this article

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Abstract

α-Synuclein misfolds into pathological forms that lead to various neurodegenerative diseases known collectively as α-synucleinopathies. In this Review, we provide a comprehensive overview of pivotal advances in α-synuclein research. We examine structural features and physiological functions of α-synuclein and summarize current insights into key post-translational modifications, such as nitration, phosphorylation, ubiquitination, sumoylation and truncation, considering their contributions to neurodegeneration. We also highlight the existence of disease-specific α-synuclein strains and their mechanisms of pathological spread, and discuss seed amplification assays and PET tracers as emerging diagnostic tools for detecting pathological α-synuclein in clinical settings. We also discuss α-synuclein aggregation and clearance mechanisms, and review cell-autonomous and non-cell-autonomous processes that contribute to neuronal death, including the roles of adaptive and innate immunity in α-synuclein-driven neurodegeneration. Finally, we highlight promising therapeutic approaches that target pathological α-synuclein and provide insights into emerging areas of research.

Key points

  • α-Synuclein can self-aggregate, oligomerize and fibrillize into different pathological strains that are associated with various α-synucleinopathies.

  • Parkinson disease and related α-synucleinopathies are widely thought to be prion-like disorders, in which α-synuclein pathology spreads via a templating mechanism.

  • Neurodegeneration that results from pathological α-synuclein is mediated by cell-autonomous and non-cell-autonomous mechanisms.

  • Parthanatos is the main cell death pathway by which pathological α-synuclein induces neurodegeneration.

  • Pathological α-synuclein molecular pathway analysis has created new therapeutic opportunities for Parkinson disease and related α-synucleinopathies.

  • PET imaging and α-synuclein seed amplification assays will guide future clinical studies by enabling the monitoring of α-synuclein pathology and responses to therapy.

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Fig. 1: Timeline of key advances in the field of α-synuclein biology and pathobiology.
Fig. 2: Structure of α-synuclein with alterations associated with Parkinson disease.
Fig. 3: Characteristics of body-first and brain-first Parkinson disease.
Fig. 4: Pathways of α-synuclein-related neurodegeneration and possible interventions.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health/National Institute on Aging AG085688, the JPB Foundation, Aligning Science Across Parkinson’s (020608) through the Michael J. Fox Foundation for Parkinson’s Research, Farmer Family Foundation Parkinson’s Research Initiative, Robert J. and Claire Pasarow Foundation, Parkinson’s Foundation and the National Research Foundation of Korea (RS-2023-00278580). The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with the Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Program M-2019 and H-2021, respectively. T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases.

Author information

Author notes

  1. These authors contributed equally: Hyejin Park, Tae-In Kam.

  2. These authors jointly supervised this work: Valina L. Dawson, Ted M. Dawson.

Authors and Affiliations

  1. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Hyejin Park, Tae-In Kam, Valina L. Dawson & Ted M. Dawson

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Hyejin Park, Tae-In Kam, Valina L. Dawson & Ted M. Dawson

  3. Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA

    Hyejin Park, Tae-In Kam, Valina L. Dawson & Ted M. Dawson

  4. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Hyejin Park

  5. Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Tae-In Kam

  6. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Valina L. Dawson & Ted M. Dawson

  7. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Valina L. Dawson

  8. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ted M. Dawson

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  1. Hyejin Park
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Contributions

H.P., T.-I.K. and T.M.D. researched data for the article and wrote the article. V.L.D. and T.M.D. reviewed and edited the manuscript before submission. All authors made substantial contributions to discussion of the content.

Corresponding author

Correspondence to Ted M. Dawson.

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T.M.D. owns stock in Aevum Therapeutics and stock options in D&D Pharmatech, Inhibikase Therapeutics and Ventyx Biosciences; holds equity in D&D Pharmatech; is compensated for his role on the scientific advisory boards of Aevum and Ventyx; is entitled to royalties from AbbVie; and is a founder and inventor of technology for Neuraly, which is now a subsidiary of D&D Pharmatech. V.L.D. owns stock options in D&D Pharmatech and Inhibikase Therapeutics; holds equity in D&D Pharmatech; and is a founder and inventor of technology for Neuraly, which is now a subsidiary of D&D Pharmatech. The other authors declare no competing interests.

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Park, H., Kam, TI., Dawson, V.L. et al. α-Synuclein pathology as a target in neurodegenerative diseases. Nat Rev Neurol 21, 32–47 (2025). https://doi.org/10.1038/s41582-024-01043-w

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