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

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

doi:10.1038/nm.3736

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

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

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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, 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 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
Pages (from-to)	1452-1457
Number of pages	6
Journal	Nature medicine
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/nm.3736
State	Published - Dec 1 2014

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Wetzel-Smith, M. K., Hunkapiller, J., Bhangale, T. R., Srinivasan, K., Maloney, J. A., Atwal, J. K., Sa, S. M., Yaylaoglu, M. B., Foreman, O., Ortmann, W., Rathore, N., Hansen, D. V., Tessier-Lavigne, M., Mayeux, R., Pericak-Vance, M., Haines, J., Farrer, L. A., Schellenberg, G. D., Goate, A., ... Graham, R. R. (2014). A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death. Nature medicine, 20(12), 1452-1457. https://doi.org/10.1038/nm.3736

@article{7bc3cb6a6bbc4680beb3698d9f8b7188,

title = "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 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.",

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

year = "2014",

month = dec,

day = "1",

doi = "10.1038/nm.3736",

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Wetzel-Smith, MK, Hunkapiller, J, Bhangale, TR, Srinivasan, K, Maloney, JA, Atwal, JK, Sa, SM, Yaylaoglu, MB, Foreman, O, Ortmann, W, Rathore, N, Hansen, DV, Tessier-Lavigne, M, Mayeux, R, Pericak-Vance, M, Haines, J, Farrer, LA, Schellenberg, GD, Goate, A, Behrens, TW, Cruchaga, C, Watts, RJ & Graham, RR 2014, 'A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death', Nature medicine, vol. 20, no. 12, pp. 1452-1457. https://doi.org/10.1038/nm.3736

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

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.

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U2 - 10.1038/nm.3736

DO - 10.1038/nm.3736

M3 - Article

C2 - 25419706

AN - SCOPUS:84937526426

SN - 1078-8956

VL - 20

SP - 1452

EP - 1457

JO - Nature medicine

JF - Nature medicine

IS - 12

ER -

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

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