A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death

Monica K. Wetzel-Smith, Julie Hunkapiller, Tushar R. Bhangale, Karpagam Srinivasan, Janice A. Maloney, Jasvinder K. Atwal, Susan M. Sa, Murat B. Yaylaoglu, Oded Foreman, Ward Ortmann, Nisha Rathore, David V. Hansen, Marc Tessier-Lavigne, Richard Mayeux, Margaret Pericak-Vance, Jonathan Haines, Lindsay A. Farrer, Gerard D. Schellenberg, Alison Goate, Timothy W. BehrensCarlos Cruchaga, Ryan J. Watts, Robert R. Graham

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1452-1457
Number of pages6
JournalNature medicine
Issue number12
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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