Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications

J Parkinsons Dis. 2024;14(7):1301-1329. doi: 10.3233/JPD-240195.

Abstract

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies.

Keywords: Parkinson’s disease; infections; multiple system atrophy; α-synuclein.

Plain language summary

This review explores how infections might contribute to the development of Parkinson’s disease and other synucleinopathies. It highlights evidence that microbial pathogens may trigger neurodegeneration by causing neuroinflammation. We emphasize the complex relationship between infections, genetics, and neurodegeneration, and discuss how understanding these connections could lead to earlier diagnosis and new treatments. In this review we also identify key knowledge gaps, and we suggest areas for future research.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Infections / etiology
  • Infections / immunology
  • Neuroinflammatory Diseases / etiology
  • Neuroinflammatory Diseases / immunology
  • Parkinson Disease* / etiology
  • Parkinson Disease* / immunology
  • Synucleinopathies* / etiology
  • Synucleinopathies* / immunology
  • Synucleinopathies* / metabolism
  • Synucleinopathies* / therapy
  • alpha-Synuclein* / metabolism

Substances

  • alpha-Synuclein