A specific amino acid motif ofHLA-DRB1mediates risk and interacts with smoking history in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70–74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the “shared epitope” (SE), the residues Q/R-K/R-R-A-A at positions 70–74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10−4; odds ratio, 0.51; 95% confidence interval, 0.36–0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08–2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.

Glycosphingolipids and neuroinflammation in Parkinson’s disease

“…in the brain of patients with Parkinson's disease [8]. Second, specific HLA variants HLA-DRA and HLA-DRB1 are associated to the etiology of Parkinson's disease [9,10]. Third, microglial cell activation can be triggered experimentally by Parkinson's disease-causing gene products such as alpha-synuclein [11,12].…”

“…First, classical activation of microglial cells, the resident mononuclear phagocytes of the central nervous system [ 7 ], is constantly observed in the brain of patients with Parkinson’s disease [ 8 ]. Second, specific HLA variants HLA-DRA and HLA-DRB1 are associated to the etiology of Parkinson’s disease [ 9 , 10 ]. Third, microglial cell activation can be triggered experimentally by Parkinson’s disease-causing gene products such as alpha-synuclein [ 11 , 12 ].…”

Common Neurodegeneration-Associated Proteins Are Physiologically Expressed by Human B Lymphocytes and Are Interconnected via the Inflammation/Autophagy-Related Proteins TRAF6 and SQSTM1

“…Extending the functional results mentioned above, genome-wide association studies (GWAS) have unraveled the central position of autoimmunity-related genes in the genetic susceptibility landscape of neurodegenerative diseases (14–19). This is notably the case for HLA-DRB1 alleles which were recently demonstrated to confer increased risks of developing PD (15) or late-onset AD (14). Also, two genes involved in familial forms of PD, namely PINK1 (PTEN-induced putative kinase 1) and PRKN (Parkin RBR E3 Ubiquitin Protein Ligase also named PARK2 or Parkin) were shown to regulate the presentation of mitochondria-derived antigens in the context of MHC class I molecules (20).…”

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

“…Extending the functional results mentioned above, genome-wide association studies (GWAS) have unraveled the central position of autoimmunity-related genes in the genetic susceptibility landscape of neurodegenerative diseases (14)(15)(16)(17)(18)(19). This is notably the case for HLA-DRB1 alleles which were recently demonstrated to confer increased risks of developing PD (15) or late-onset AD (14).…”

“…Extending the functional results mentioned above, genome-wide association studies (GWAS) have unraveled the central position of autoimmunity-related genes in the genetic susceptibility landscape of neurodegenerative diseases (14)(15)(16)(17)(18)(19). This is notably the case for HLA-DRB1 alleles which were recently demonstrated to confer increased risks of developing PD (15) or late-onset AD (14). Further supporting the hypothesis of an autoimmune/neurodegeneration pathway, two genes involved in familial forms of PD, namely PINK1 (PTEN-induced putative kinase 1) and PRKN (Parkin RBR E3 Ubiquitin Protein Ligase also named PARK2 or Parkin) were shown to regulate the presentation of mitochondria-derived antigens in the context of MHC class I molecules (20).…”