Differential Peripheral NLRP3 Inflammasome Expression in Patients With Parkinson's Disease and Patients With Multiple...

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been proposed to be a downstream mediator of neuroinflammation in individuals with 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 the peripheral mRNA expression of NLRP3-related genes and cytokines across individuals with isolated REM sleep behavior disorder (iRBD), early-stage PD, late-stage PD, and MSA.

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

NLRP3 expression was significantly lower in patients with iRBD (p=0.0263) and patients with early-stage PD (p= 0.0101) than in HCs. NIMA-related kinase 7 (NEK7) expression progressively decreased across the disease spectrum (HCs vs. patients with early-stage PD, p=0.0008; vs. patients with late-stage PD, p<0.0001). In contrast, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 were elevated in patients with PD, especially those in the late stages. Levels of patients with MSA resembled those of HCs but differed from those of patients with PD. Interleukin (IL)-1β and IL-18 levels were not significantly different. In patients with early-stage PD, NLRP3 expression was negatively correlated with disease duration, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part II score, and the cognitive score.

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.