Immune System and Neuroinflammation in Idiopathic Parkinson’s Disease: Association Analysis of Genetic Variants and miRNAs Interactions

Abstract

The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of idiopathic Parkinson’s Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated with PD susceptibility. Of them, 12 SNPs were described as significant expression Quantitative Loci (eQTL) variants in different brain regions associated with motor and non-motor PD phenomenology. Moreover, the study highlighted 11 novel susceptibility genes for PD, which may alter multiple signaling pathways critically involved in peripheral immune response, neuroinflammation, neurodegeneration and dopaminergic neurons wiring. The study of miRNA-target genes highlighted a possible role of miR-499a, miR-196a2, and miR-29a in the modulation of multiple neuroinflammatory and neurodegenerative mechanisms underlying PD physiopathology. The study described a network of interconnected genes (APOE, CLU, IL6, IL7R, IL12B, INPP5D, MAPK1, MEF2C, MIF, and TNFSF14), which may act as upstream regulators in the modulation of biological pathways relevant to PD. Intriguingly, IL6 stands out as a master gene regulator since it may indirectly regulate the network of interconnected genes. The study highlighted different genes and miRNAs interactions potentially involved in PD physiopathology, which are worth to be further explored to improve the knowledge of disease and the research of novel treatments strategies.

Autoimmune Disease Associated CLEC16A Variants Convey Risk of Parkinson’s Disease in Han Chinese

“…Our results show that rs6498169 and rs7200786 are associated with PD susceptibility. The modulation of rs7200786 on PD risk is consistent with a previous report in the Italian population ( Strafella et al, 2021 ). The A of rs6498169 and the G of rs7200786 are recessive risk alleles.…”

CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

“…Unlike other CLEC proteins, CLEC16A lacks an active/full length carbohydrate recognition domain and functions as an E3-ubiquitin ligase involved in the regulation of autophagy and mitophagy (Kim et al 2010Pearson et al 2018;Redmann et al 2016;Soleimanpour et al 2014). Despite the absence of a functional carbohydrate recognition domain, several GWAS studies have shown a link between CLEC16A and the human immune system by associating the CLEC16A locus with susceptibility to auto-immune diseases, including type-1 diabetes (Hakonarson et al 2007;Wellcome Trust Case Control Consortium 2007), multiple sclerosis (International Multiple Sclerosis Genetics Consortium 2009;International Multiple Sclerosis Genetics Consortium et al 2007;Nischwitz et al 2011), primary biliary cholangitis (Hirschfield et al 2012), Addison disease (Skinningsrud et al 2008), juvenile idiopathic arthritis (Skinningsrud et al 2010), and neurodegenerative disorders like Parkinson disease (Fan et al 2022;Strafella et al 2021). CLEC16A is thought to regulate immune tolerance via the endosome-lysosome trafficking by stimulating autophagy of thymic epithelial cells and lowering of the antigen-presenting function (Schuster et al 2015), by the regulation of HLA class-II antigen expression via late endosome biogenesis in antigen-presenting cells and by participating in retrograde transport of HLA-II containing compartments in myeloid cells (Li et al 2015;Rijvers et al 2020;van Luijn et al 2015).…”

Deregulation of ncRNA in Neurodegenerative Disease: Focus on circRNA, lncRNA and miRNA in Amyotrophic Lateral Sclerosis

“…MicroRNAs (miRNAs) are small oligonucleotide sequences (about 19–22 base pairs) of single-stranded non-coding RNA, which play a crucial function by regulating gene expression at post-transcriptional level ( Figure 1 ). The action of miRNAs has been suggested as a mechanism to regulate neuroinflammation in different NDs including ALS ( Benigni et al, 2016 ; Bai et al, 2017a ; Wang et al, 2020 ; Strafella et al, 2021a ; Strafella et al, 2021b ).…”