Journal
NATURE MEDICINE
Volume 20, Issue 12, Pages 1452-1457Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3736
Keywords
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Funding
- US National Institutes of Health [R01-AG044546, P50-AG05681]
- Alzheimer's Association [NIRG-11-200110]
- American Federation for Aging Research
- BrightFocus Foundation Alzheimer's Disease Research grant [A2013359S]
- National Institute on Aging (NIA) [U24 AG21886]
- NIA [U24 AG026395, UO1AG032984]
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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, P-meta = 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 p-amyloid (A beta), 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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