Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions

Grace Kuo; Ramhari Kumbhar; William Blair; Valina L Dawson; Ted M Dawson; Xiaobo Mao

doi:10.1186/s13024-025-00797-1

Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions

Mol Neurodegener. 2025 Jan 23;20(1):10. doi: 10.1186/s13024-025-00797-1.

Authors

Grace Kuo^{1

2}, Ramhari Kumbhar^{1

2}, William Blair^{1

2}, Valina L Dawson^{3

4

5

6

7}, Ted M Dawson^{8

9

10

11

12}, Xiaobo Mao^{13

14

15

16

17}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson1@jhmi.edu.
⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson1@jhmi.edu.
⁵ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. vdawson1@jhmi.edu.
⁶ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson1@jhmi.edu.
⁷ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson1@jhmi.edu.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹⁰ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹¹ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹² Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. xmao4@jhmi.edu.
¹⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. xmao4@jhmi.edu.
¹⁵ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. xmao4@jhmi.edu.
¹⁶ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA. xmao4@jhmi.edu.
¹⁷ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA. xmao4@jhmi.edu.

Abstract

α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer's disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies.

Keywords: Prion-like; Receptor; Spreading; Therapeutic targets; α-synuclein.

Publication types

Review

MeSH terms

Animals
Humans
Synucleinopathies* / metabolism
Synucleinopathies* / pathology
alpha-Synuclein* / metabolism

Substances

alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding