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A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.
- Source :
-
Nature medicine [Nat Med] 2014 Dec; Vol. 20 (12), pp. 1452-7. Date of Electronic Publication: 2014 Nov 24. - Publication Year :
- 2014
-
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.
- Subjects :
- Aged
Aged, 80 and over
Amyloid beta-Peptides
Animals
CA3 Region, Hippocampal cytology
Cell Death genetics
Female
Genetic Predisposition to Disease
Glutamic Acid
HEK293 Cells
Humans
Male
Mice
Netrin Receptors
Rats
Staurosporine
Alzheimer Disease genetics
Neurons metabolism
Receptors, Cell Surface genetics
Receptors, Nerve Growth Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 20
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25419706
- Full Text :
- https://doi.org/10.1038/nm.3736