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Nat Med. 2014 Dec;20(12):1452-7. doi: 10.1038/nm.3736. Epub 2014 Nov 24.

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

Author information

1
Department of Neuroscience, Genentech, South San Francisco, California, USA.
2
Department of Human Genetics, Genentech, South San Francisco, California, USA.
3
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, USA.
4
Department of Pathology, Genentech, South San Francisco, California, USA.
5
Laboratory of Brain Development and Repair, Rockefeller University, New York, New York, USA.
6
1] Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA. [2] Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
7
1] The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA. [2] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.
8
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
9
1] Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [2] Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [3] Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [4] Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. [5] Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
10
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
11
1] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA. [3] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
12
1] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.

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.

PMID:
25419706
PMCID:
PMC4301587
DOI:
10.1038/nm.3736
[Indexed for MEDLINE]
Free PMC Article

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