title: The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane.
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.
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Graduate Program in Molecular Translational Medicine, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, United States of America.
authors: Michael W
authors: MW
authors: Nagle
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, United States of America.
authors: Jeanne C
authors: JC
authors: Latourelle
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Bioinformatics Program, Boston University College of Arts and Sciences, Boston, MA, 02118, United States of America.
authors: Adam
authors: A
authors: Labadorf
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, United States of America.
authors: Alexandra
authors: A
authors: Dumitriu
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.
authors: Tiffany C
authors: TC
authors: Hadzi
authors: Banner Sun Health Research Institute, Sun City, Arizona, 85351, United States of America.
authors: Thomas G
authors: TG
authors: Beach
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Graduate Program in Molecular Translational Medicine, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, United States of America.|Bioinformatics Program, Boston University College of Arts and Sciences, Boston, MA, 02118, United States of America.
authors: Richard H
authors: RH
authors: Myers
mesh_terms: D001921:Brain / Q000473:pathology; D002894:Chromosomes, Human, Pair 4; D005091:Exons; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013572:Synaptic Vesicles / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases