title: A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.
abstract: We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: Monica K
authors.initials: MK
authors.lastname: Wetzel-Smith
authors.affiliation: Department of Human Genetics, Genentech, South San Francisco, California, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Hunkapiller
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, USA.
authors.forename: Tushar R
authors.initials: TR
authors.lastname: Bhangale
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: Karpagam
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Maloney
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: Jasvinder K
authors.initials: JK
authors.lastname: Atwal
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sa
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Murat B
authors.initials: MB
authors.lastname: Yaylaoglu
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Human Genetics, Genentech, South San Francisco, California, USA.
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.affiliation: Department of Human Genetics, Genentech, South San Francisco, California, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Rathore
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Hansen
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: 1] Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA. [2] Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: 1] The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA. [2] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haines
authors.affiliation: 1] Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [2] Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [3] Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [4] Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [5] Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: 1] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA. [3] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Human Genetics, Genentech, South San Francisco, California, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: 1] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: Department of Human Genetics, Genentech, South San Francisco, California, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000166:cytology; D016923:Cell Death / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D000075386:Netrin Receptors; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D019311:Staurosporine
chemical_list: D016229:Amyloid beta-Peptides; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; C115727:UNC5C protein, human; C000595076:UNC5C protein, rat; C105653:Unc5c protein, mouse; D018698:Glutamic Acid; D019311:Staurosporine