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REVIEW article

Front. Aging Neurosci.

Sec. Parkinson’s Disease and Aging-related Movement Disorders

Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1600782

Parkinson's Disease Beyond the Brain: Implications for Treatments

Provisionally accepted
Setareh Malekian NaeiniSetareh Malekian Naeini1,2Marc Danzell LopezMarc Danzell Lopez1,3Leila Safaee ArdekaniLeila Safaee Ardekani3Paul E FraserPaul E Fraser3,4Anurag TandonAnurag Tandon1,3*
  • 1University of Toronto, Toronto, Canada
  • 2Department of Physiology, University of Toronto, Toronto, Canada
  • 3Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
  • 4Department of Medical Biophysics, University of Toronto, Toronto, Canada

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The presence of α-synuclein pathology in peripheral nervous system neurons is linked to early prodromal, non-motor symptoms in a segment of Parkinson's disease (PD) patients referred to as 'body-first'. These features of the disease suggest a convergence of environmental, genetic, immune and age-related factors within the enteric nervous system as initiating triggers of disease. This review explores the changes in the gut microbiome and intestinal permeability that may drive systemic inflammation and precede neurodegeneration in PD. The pathways leading to the formation of α-synuclein aggregates are explored as well as their role in transneuronal propagation and the spreading of pathology within the brain. Lastly, advances in systemic gene therapy that could be used to target multiple PD-affected organs following systemic injection are highlighted. By integrating insights from molecular biology and clinical research, it may be possible to shed light on the multifactorial etiology of PD and the interconnectedness of the gut and brain, which could lead to novel diagnostic and therapeutic strategies.

Keywords: Synucleinopathy, Enteric neurons, Aggregation, Lewy bodies, Gastrointestinal tract Parkinson's Disease, α-Synuclein, gut dysbiosis, enteric nervous system prion-like propagation, Neuroinflammation, Gene Therapy

Received: 26 Mar 2025; Accepted: 28 Aug 2025.

Copyright: © 2025 Naeini, Lopez, Ardekani, Fraser and Tandon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Anurag Tandon, University of Toronto, Toronto, Canada

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material