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Title | A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Wetzel-Smith MK, Hunkapiller J, Bhangale TR, Srinivasan K, Maloney JA, Atwal JK, Sa SM, Yaylaoglu MB, Foreman O, Ortmann W, Rathore N, Hansen DV, Tessier-Lavigne M, Mayeux R, Pericak-Vance M, Haines J, Farrer LA, Schellenberg GD, Goate A, Behrens TW, Cruchaga C, Watts RJ, Graham RR |
Corporate Authors | Alzheimer's Disease Genetics Consortium |
Journal | Nat Med |
Volume | 20 |
Issue | 12 |
Pagination | 1452-7 |
Date Published | 2014 Dec |
ISSN | 1546-170X |
Keywords | Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Animals, CA3 Region, Hippocampal, Cell Death, Female, Genetic Predisposition to Disease, Glutamic Acid, HEK293 Cells, Humans, Male, Mice, Netrin Receptors, Neurons, Rats, Receptors, Cell Surface, Receptors, Nerve Growth Factor, Staurosporine |
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. |
DOI | 10.1038/nm.3736 |
Alternate Journal | Nat. Med. |
PubMed ID | 25419706 |
PubMed Central ID | PMC4301587 |
Grant List | R01 AG044546 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States UO1AG032984 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States R01-AG044546 / AG / NIA NIH HHS / United States / / Howard Hughes Medical Institute / United States R01 AG041797 / AG / NIA NIH HHS / United States P50-AG05681 / AG / NIA NIH HHS / United States U24 AG21886 / AG / NIA NIH HHS / United States |