Differential Peripheral NLRP3 Inflammasome Expression in Parkinson's Disease and Multiple System Atrophy.

Objective: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been proposed as a downstream mediator of neuroinflammation in Parkinson's disease (PD). However, its involvement across disease stages and related synucleinopathies such as multiple system atrophy (MSA) remains unclear. We aimed to analyze peripheral mRNA expression of NLRP3-related genes and cytokines across isolated REM sleep behavior disorder (iRBD), early and late-stage PD, and MSA.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 151 participants: 35 healthy controls (HCs), 31 iRBD, 41 early PD, 21 late PD, and 23 MSA. mRNA expression was measured using quantitative real-time polymerase chain reaction (qPCR). Statistical comparisons were performed using ANOVA or Welch's ANOVA, and associations with clinical variables were analyzed through stepwise multiple linear regression.

Results: NLRP3 expression was significantly reduced in iRBD (p = 0.0263) and early PD (p = 0.0101) compared to HCs. NIMA-related kinase 7 (NEK7) showed a progressive decrease (HCs vs. early PD, p = 0.0008; vs. late PD, p < 0.0001). In contrast, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 were elevated in PD, especially in late stages. MSA resembled HCs but differed from PD. Interleukin (IL)-1β and IL-18 levels were not significantly different. In early PD, NLRP3 expression negatively correlated with disease duration, MDS-UPDRS Part II, and cognitive scores.

Conclusion: Our findings challenge the prevailing hypothesis that NLRP3 inflammasome activation directly contributes to PD pathogenesis. Instead, the observed increase in ASC and caspase-1 expression suggests the potential involvement of alternative inflammasome pathways during disease progression.