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

Abstract

We have identified a rare coding mutation, T835M (rs137875858), in the Netrin receptor UNC5C that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer’s disease (LOAD), and was associated with disease across four large case/control cohorts (OR = 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 several cell types, including neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to multiple neurodegenerative stimuli, including β-Amyloid (Aβ). Based on these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose 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 brain.

An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling

“…1-3), whereas the percentages of dead HEK293T cells and primary rat hippocampal neurons that exogenously expressed T835M-UNC5C were ϳ25 and 50% at the harvest time in the previous study (17). Given that the transfection efficiency in our experiments using F11 cells and SH-SY5Y cells is 80% or more, the death-inducing activity of T835M-UNC5C is estimated to be slightly higher in our neuronal cell lines than in those reported previously (17).…”

“…Interestingly, a study demonstrated that the expression of DAPK increased in the brains of some AD patients (41). The mutant form of UNC5C is present as a risk factor (17) throughout life, although the disease occurs later in the life. The mechanism underlying the effect of aging on the disease onset remains to be investigated.…”

“…Interestingly, T835M-UNC5C did not increase the production of A␤ but increased the vulnerability of neuronal cells to various insults (17). The molecular mechanism underlying the T835M-UNC5C-mediated increase in neuronal toxicity remains uncharacterized.…”

“…It was recently reported that a missense mutation of a singlespanning transmembrane protein uncoordinated-5 homologue C (UNC5C; alternative name UNC5H3), a netrin receptor (14 -16), increases the risk of late-onset AD (17), although the prevalence of its mutation in AD patients is low (17). Interestingly, T835M-UNC5C did not increase the production of A␤ but increased the vulnerability of neuronal cells to various insults (17).…”

Mutations in the netrin-1 gene cause congenital mirror movements

“…However, except for a possible association with cleft lip in GWAS studies (15), the 20th anniversary of the discovery of netrin-1 has passed without the identification of a single human disease caused by inherited mutations in NTN1, the gene coding for netrin-1. In contrast, variants in the genes coding for receptors of netrin-1 such as UNC5C have been linked to Alzheimer's disease and colorectal cancer (16), while mutations in DCC have Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood.…”