Year: 2026
Type: review
Abstract: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.
Source: Frontiers in Immunology
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Award: G2002194808
OpenAlex ID: W7212295682