Immunogenetic Determinants of Parkinson's Disease Etiology

Abstract

Parkinson's disease (PD) is increasingly recognised as a systemic disorder in which inflammation might play a causative role rather than being a consequence or an epiphenomenon of the neurodegenerative process. Although growing genetic evidence links the central and peripheral immune system with both monogenic and sporadic PD, our understanding on how the immune system contributes to PD pathogenesis remains a daunting challenge. In this review, we discuss recent literature aimed at exploring the role of known genes and susceptibility loci to PD pathogenesis through immune system related mechanisms. Furthermore, we outline shared genetic etiologies and interrelations between PD and autoimmune diseases and underlining challenges and limitations faced in the translation of relevant allelic and regulatory risk loci to immune-pathological mechanisms. Lastly, with the field of immunogenetics expanding rapidly, we place these insights into a future context highlighting the prospect of immune modulation as a promising disease-modifying strategy.

Keywords: Parkinson’s disease; immune system; immunogenetics; onset; progression; risk.

Fig. 1

Putative functional mechanisms for which PD genetic variants might contribute to the immune system regulation. Most PD risk loci span non-coding regions. When a PD risk SNP with an eQTL mechanism colocalizes with immune-related genes in topologically associating domains, immune-gene regulation will be affected by chromatin interaction. PD causing SNPs may be located in enhancers or promoters, and immune-gene regulation will be affected by trans-acting or cis-acting regulatory mechanisms.