DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Peter Sykora; Magdalena Misiak; Yue Wang; Somnath Ghosh; Giovana S. Leandro; Dong Liu; Jane Tian; Beverly A. Baptiste; Wei Na Cong; Boris M. Brenerman; Evandro Fang; Kevin G. Becker; Royce J. Hamilton; Soumya Chigurupati; Yongqing Zhang; Josephine M. Egan; Deborah L. Croteau; David M. Wilson; Mark P. Mattson; Vilhelm A. Bohr

doi:10.1093/nar/gku1356

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Peter Sykora, Magdalena Misiak, Yue Wang, Somnath Ghosh, Giovana S. Leandro, Dong Liu, Jane Tian, Beverly A. Baptiste, Wei Na Cong, Boris M. Brenerman, Evandro Fang, Kevin G. Becker, Royce J. Hamilton, Soumya Chigurupati, Yongqing Zhang, Josephine M. Egan, Deborah L. Croteau, David M. Wilson, Mark P. Mattson, Vilhelm A. Bohr

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64 Scopus citations

Abstract

We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ^+/- mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.

Original language	English (US)
Pages (from-to)	943-959
Number of pages	17
Journal	Nucleic Acids Research
Volume	43
Issue number	2
DOIs	https://doi.org/10.1093/nar/gku1356
State	Published - Jan 30 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Sykora, P., Misiak, M., Wang, Y., Ghosh, S., Leandro, G. S., Liu, D., Tian, J., Baptiste, B. A., Cong, W. N., Brenerman, B. M., Fang, E., Becker, K. G., Hamilton, R. J., Chigurupati, S., Zhang, Y., Egan, J. M., Croteau, D. L., Wilson, D. M., Mattson, M. P., & Bohr, V. A. (2015). DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Research, 43(2), 943-959. https://doi.org/10.1093/nar/gku1356

Sykora, P, Misiak, M, Wang, Y, Ghosh, S, Leandro, GS, Liu, D, Tian, J, Baptiste, BA, Cong, WN, Brenerman, BM, Fang, E, Becker, KG, Hamilton, RJ, Chigurupati, S, Zhang, Y, Egan, JM, Croteau, DL, Wilson, DM, Mattson, MP & Bohr, VA 2015, 'DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes', Nucleic Acids Research, vol. 43, no. 2, pp. 943-959. https://doi.org/10.1093/nar/gku1356

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abstract = "We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ+/- mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.",

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AU - Liu, Dong

AU - Tian, Jane

AU - Baptiste, Beverly A.

AU - Cong, Wei Na

AU - Brenerman, Boris M.

AU - Fang, Evandro

AU - Becker, Kevin G.

AU - Hamilton, Royce J.

AU - Chigurupati, Soumya

AU - Zhang, Yongqing

AU - Egan, Josephine M.

AU - Croteau, Deborah L.

AU - Wilson, David M.

AU - Mattson, Mark P.

AU - Bohr, Vilhelm A.

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DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

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