title: Regulatory region genetic variation is associated with FYN expression in Alzheimer's disease.
abstract: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau, are a key pathologic feature of Alzheimer's disease (AD). Tau phosphorylation is under the control of multiple kinases and phosphatases, including Fyn. Previously, our group found an association between 2 regulatory single nucleotide polymorphisms in the FYN gene with increased tau levels in the cerebrospinal fluid. In this study, we hypothesized that Fyn expression in the brain is influenced by AD status and genetic content. We found that Fyn protein, but not messenger RNA, levels were increased in AD patients compared to cognitively normal controls and are associated with regulatory region single nucleotide polymorphisms. In addition, the expression of the FYN 3'UTR can decrease expression in multiple cell lines, suggesting this regulatory region plays an important role in FYN expression. Taken together, these data suggest that FYN expression is regulated according to AD status and regulatory region haplotype, and genetic variants may be instrumental in the development of neurofibrillary tangles in AD and other tauopathies.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address: zahratj@ccf.org.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Zahratka
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: McKenzie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Todd
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Shane V
authors.initials: SV
authors.lastname: Formica
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Khrestian
authors.affiliation: Department of Pathology, Stanford University, Palo Alto, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Montine
authors.affiliation: Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D016875:tau Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn
keywords: Alzheimer's disease; Cerebellum; Fyn; Hippocampus; Reporter assay; SNP