α-Synuclein pathology as a target in neurodegenerative diseases

Hyejin Park; Tae-In Kam; Valina L Dawson; Ted M Dawson

doi:10.1038/s41582-024-01043-w

α-Synuclein pathology as a target in neurodegenerative diseases

Nat Rev Neurol. 2024 Nov 28. doi: 10.1038/s41582-024-01043-w. Online ahead of print.

Authors

Hyejin Park^#^{1

2

3

4}, Tae-In Kam^#^{1

2

3

5}, Valina L Dawson^{1

2

3

6

7}, Ted M Dawson^{8

9

10

11

12}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
⁴ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁵ Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁶ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
¹⁰ Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. tdawson@jhmi.edu.
¹¹ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.
¹² Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu.

^# Contributed equally.

PMID: 39609631
DOI: 10.1038/s41582-024-01043-w

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.

Publication types

Review