Parkinson's disease: exploring the systemic immune mechanisms through molecular investigations

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder that is mainly caused by the degeneration of dopaminergic neurons of the substantia nigra. Although the pathological feature involves α-synuclein aggregation, recent findings suggest that systemic immune dysregulation is a key process in initiating and advancing the disease. This article seeks to untangle the complex molecular mechanisms that contribute to the immune response in PD, with specific emphasis on innate and adaptive immune processes. α-Synuclein-induced T-cell-mediated neuronal degeneration reveals a causal relationship between peripheral immunity and central neurodegeneration. At the same time, stimulation of innate immune sensors like the NLRP3 inflammasome in microglia has been found to accelerate neuroinflammation and lead to neuronal loss. Mitochondrial dysfunction, another key hallmark of PD, leads to defective mitophagy and release of mitochondrial danger-associated molecular patterns (DAMPs), further exaggerating inflammatory signals through NLRP3 and other mechanisms. Moreover, defective autophagic and lysosomal degradation machinery may perpetuate chronic inflammation and immune cell activation. Gut microbiota-gut-associated lymphoid tissue-peripheral immune cell interaction with the blood-brain barrier also comes into play as a key player in PD neuroimmune cross-talk. We specifically address therapeutic implications, focusing on the promise of immune checkpoint targeting, inhibition of inflammasomes, and mitophagy improvement as new disease-modifying approaches. Elucidation of these complex immune mechanisms offers key insights into PD pathophysiology and opens promising immunomodulatory therapeutic paths. This review integrates cutting-edge discoveries and outlines a shared model to improve understanding of the systemic immune setting in Parkinson's disease.

Keywords: Gut–brain axis; Mitophagy; NLRP3 inflammasome; Neuroinflammation; Parkinson’s disease; Systemic immune response; α-Synuclein.