The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane

PLoS One. 2016 Aug 10;11(8):e0160925. doi: 10.1371/journal.pone.0160925. eCollection 2016.

Abstract

Genome-wide association studies (GWAS) have identified the GAK/DGKQ/IDUA region on 4p16.3 among the top three risk loci for Parkinson's disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3' clathrin-binding domain of GAK identified by RNA deep-sequencing in post-mortem human brain tissue as having increased expression in PD. Furthermore, carriers of 4p16.3 PD GWAS risk SNPs show decreased expression of one of these transcripts, GAK25 (Gencode Transcript 009), which correlates with the expression of genes functioning in the synaptic vesicle membrane. Together, these findings provide strong evidence for GAK clathrin-binding- and J-domain transcripts' influence on PD pathogenicity, and for a role for GAK in regulating synaptic function in PD.

MeSH terms

  • Brain / pathology
  • Chromosomes, Human, Pair 4*
  • Exons
  • Gene Expression
  • Genome-Wide Association Study
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mitochondria / genetics
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Polymorphism, Single Nucleotide*
  • Protein Serine-Threonine Kinases / genetics*
  • Synaptic Vesicles / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • GAK protein, human
  • Protein Serine-Threonine Kinases