REVIEW article
Front. Aging Neurosci.
Sec. Parkinson’s Disease and Aging-related Movement Disorders
This article is part of the Research TopicNeurochemical and neuroimaging α-Synuclein dynamics in cellular and molecular mechanisms of brain agingView all articles
PARKINSON'S DISEASE PHYSIOPATHOLOGY - BEYOND THE α-SYNUCLEIN AGGREGATION - A NARRATIVE REVIEW
Provisionally accepted
- 1Santa Casa de Misericordia de Maceio, Maceió, Brazil
- 2Universidade Federal de Alagoas, Maceió, Brazil
- 3Universidade UNIMA, Maceió, Brazil
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Background: Parkinson's disease (PD) is traditionally defined by dopaminergic degeneration and α-synuclein aggregation. However, mounting evidence supports a multifactorial and systemic pathophysiology that extends beyond the central nervous system. This narrative review explores the interconnected mechanisms underlying sporadic PD, including environmental exposures, gut dysbiosis, α-synuclein pathology and propagation, systemic and neuroinflammation, metabolic dysfunctions (notably insulin and lipid metabolism), sleep disturbances, glymphatic impairment, and proteostatic failure. Results: The review highlights how α-synuclein pathology can originate peripherally, particularly in the enteric nervous system, and propagate to the brain via neuronal or hematogenous routes. It also examines the synergistic roles of systemic inflammation, immune dysregulation, mitochondrial dysfunction, and impaired protein clearance in promoting neurodegeneration. Conclusion: Collectively, these findings support a reconceptualization of PD as a systemic neurodegenerative disorder involving complex crosstalk between peripheral and central pathways. Understanding these multifaceted interactions opens new avenues for early diagnosis, biomarker discovery, and disease-modifying therapeutic strategies targeting the gut-brain axis, metabolic homeostasis, and proteostasis.
Keywords: Disbiosis, Neuroinflammation, Lipid Metabolism, Glymphatic system, Oxidative Stress, Pathology
Received: 11 Jul 2025; Accepted: 03 Nov 2025.
Copyright: © 2025 Macedo, Coelho and Macedo. 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: Victor Fellipe Bispo Macedo, victorfmacedo@gmail.com
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