A rare mutation in UNC5C predisposes to late-onset Alzheimer%26apos;s disease and increases neuronal cell death

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

来源：Nature Medicine, 2014, 20(12): 1452-1457.

DOI：10.1038/nm.3736

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%26apos;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%26apos;s disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer%26apos;s disease brain.

• 出版日期2014-12