NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson’s disease

Abstract

Neuroinflammation is a well-characterized pathophysiology occurring in association with the progression of Parkinson’s disease. Characterizing the cellular and molecular basis of neuroinflammation is critical to understanding its impact on the incidence and progression of PD and other neurologic disorders. Inflammasomes are intracellular pro-inflammatory pattern-recognition receptors capable of initiating and propagating inflammation. These cellular complexes are well characterized in the innate immune system and activity of the NLRP3 inflammasome has been reported in microglia. NLRP3 inflammasome activity has been associated with Alzheimer’s disease, and recent reports, from our laboratory and others, indicate that Nlrp3 is required for neuroinflammation and nigral cell loss in animal models of PD. NLRP3 has not yet been characterized in PD patients. Here we characterize NLRP3 in PD using immunohistologic and genetic approaches. Histologic studies revealed elevated NLRP3 expression in mesencephalic neurons of PD patients. Analysis of exome sequencing data for genetic variation of NLRP3 identified multiple single-nucleotide polymorphisms (SNPs) including rs7525979 that was associated with a significantly reduced risk of developing PD. Mechanistic studies conducted in HEK293 cells indicated that the synonymous SNP, NLRP3 rs7525979, alters the efficiency of NLRP3 translation impacting NLRP3 protein stability, ubiquitination state, and solubility. These data provide evidence that dopaminergic neurons are a cell-of-origin for inflammasome activity in PD and are consistent with recent animal studies, suggesting that inflammasome activity may impact the progression of PD.

Neuroinflammation: a desirable genetic variant

A genetic variant of a protein that mediates neuroinflammatory processes reduces the risk of developing Parkinson’s disease (PD). Previous studies have shown that NLRP3 contributes to the progression of Alzheimer’s disease and PD in animal models. Matthew Havrda at the Geisel School of Medicine at Dartmouth, New Hampshire, USA, and colleagues found high levels of NLRP3 in degenerating dopaminergic neurons in the brains of patients with PD. Interestingly, analyses of genetic sequences coding NLRP3 obtained from the Parkinson’s Progression Markers Initiative revealed an NLRP3 variant associated with a significantly decreased risk of PD. This effect might be due to its reduced activity as the NLRP3 variant formed insoluble aggregates in cells. Further understanding the role of NLRP3 in neurodegenerative diseases could aid the development of novel neuroinflammatory inhibitors.