title: Genes associated with the progression of neurofibrillary tangles in Alzheimer's disease.
abstract: The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N=13), I-II (N=20), III-IV (N=19) and V-VI (N=19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N=30), and in patients with late-onset AD (N=37), dementia with Lewy bodies (N=17) and Parkinson disease (N=36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development.
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Research Association for Biotechnology, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakaya
authors.affiliation: Department of Pathology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Research Association for Biotechnology, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsukie
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hara
authors.affiliation: Department of Health Record Informatics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogishima
authors.affiliation: Department of Medical Informatics, Niigata University, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Department of Medical Informatics, Niigata University, Niigata, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Akazawa
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikeuchi
authors.affiliation: Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kuwano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001921:Brain / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D063990:Gene Ontology; D005796:Genes / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D024701:Myosin Type V / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D051546:Cyclooxygenase 2; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024701:Myosin Type V; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C099655:GRB14 protein, human; C459104:MYO5C protein, human; C481603:NPAS4 protein, human; C569112:TRIL protein, human; C496540:PTGS2 protein, human; C000717127:RELN protein, human