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 (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 language | English (US) |
|---|---|
| Pages (from-to) | 1452-1457 |
| Number of pages | 6 |
| Journal | Nature Medicine |
| Volume | 20 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2014 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death. / 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 A; Haines, Jonathan; Farrer, Lindsay A.; Schellenberg, Gerard D.; Goate, Alison; Behrens, Timothy W.; Cruchaga, Carlos; Watts, Ryan J.; Graham, Robert R.
In: Nature Medicine, Vol. 20, No. 12, 01.12.2014, p. 1452-1457.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death
AU - Wetzel-Smith, Monica K.
AU - Hunkapiller, Julie
AU - Bhangale, Tushar R.
AU - Srinivasan, Karpagam
AU - Maloney, Janice A.
AU - Atwal, Jasvinder K.
AU - Sa, Susan M.
AU - Yaylaoglu, Murat B.
AU - Foreman, Oded
AU - Ortmann, Ward
AU - Rathore, Nisha
AU - Hansen, David V.
AU - Tessier-Lavigne, Marc
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A
AU - Haines, Jonathan
AU - Farrer, Lindsay A.
AU - Schellenberg, Gerard D.
AU - Goate, Alison
AU - Behrens, Timothy W.
AU - Cruchaga, Carlos
AU - Watts, Ryan J.
AU - Graham, Robert R.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84937526426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937526426&partnerID=8YFLogxK
U2 - 10.1038/nm.3736
DO - 10.1038/nm.3736
M3 - Article
C2 - 25419706
AN - SCOPUS:84937526426
VL - 20
SP - 1452
EP - 1457
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 12
ER -