TY - JOUR
T1 - A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death
AU - Wetzel-Smith, Monica K.
AU - Hunkapiller, Julie
AU - Bhangale, Tushar R.
AU - Srinivasan, Karpagam
AU - Maloney, Janice A.
AU - Atwal, Jasvinder K.
AU - Sa, Susan M.
AU - Yaylaoglu, Murat B.
AU - Foreman, Oded
AU - Ortmann, Ward
AU - Rathore, Nisha
AU - Hansen, David V.
AU - Tessier-Lavigne, Marc
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret
AU - Haines, Jonathan
AU - Farrer, Lindsay A.
AU - Schellenberg, Gerard D.
AU - Goate, Alison
AU - Behrens, Timothy W.
AU - Cruchaga, Carlos
AU - Watts, Ryan J.
AU - Graham, Robert R.
N1 - Funding Information:
This work was partially supported by grants from the US National Institutes of Health (R01-AG044546, P50-AG05681), and the Alzheimer’s Association (NIRG-11-200110). This research was conducted while C.C. was a recipient of a New Investigator Award in Alzheimer’s disease from the American Federation for Aging Research. C.C. is a recipient of a BrightFocus Foundation Alzheimer’s Disease Research grant (A2013359S). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. NIA-LOAD samples were collected under a cooperative agreement grant (U24 AG026395) awarded by the NIA. The ADGC is funded by the NIA (UO1AG032984). We thank K. Steffansøn and DeCode Genetics for genotype counts of UNC5C variants in the Icelandic population, the Alzheimer’s Disease Centers, who collected samples used in this study, and patients and their families, whose help and participation made this work possible. We thank J. Norton of the Genetics Core, Washington University. We also thank C. Nelson (Genentech) for the HEK293 wild-type human APP695 stable cell line, K. Hoyte, Y. Lu, M. Sagolla, L. Gilmor, J. Borneo, E. Ladi, J. Grogan, J. Larson and J. Kaminker for technical assistance, and S. Ackerman, The Jackson Laboratory/Howard Hughes Medical Institute, for the generous gift of Unc5c−/− mice.
Publisher Copyright:
© 2014 Nature America, Inc. All rights reserved.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 (β2), 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.
AB - 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 (β2), 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.
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U2 - 10.1038/nm.3736
DO - 10.1038/nm.3736
M3 - Article
C2 - 25419706
AN - SCOPUS:84937526426
VL - 20
SP - 1452
EP - 1457
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 12
ER -