The goal of the proposal is to determine whether DNA DSBR are killing neurons. DNA repair bas been linked directly to Huntington Disease (HD) onset by genome-wide association studies (GWAS) in patients. CAG expansion occurs in the process of repairing oxidative DNA damage, and its role for DNA repair was well established in mouse models. During the past funding cycle, however, we have discovered that mhtt suppresses DNA repair in brain cells in a cell-type and region-specific manner in the brains of HdhQ(150/150) animals. This had modest effect on CAG expansion, but at the same time, resulted in the accumulation of DNA double strand breaks (DSBs) that had gone undetected. DSBs are the most toxic of lesions, and if not repaired lead to cell death. This raised the issue as to whether the unrepaired and previously unrecognized DSBs were responsible for killing neurons. We have developed a new approach to defining DNA repair alterations in brain cells, called repair fingerprinting.
In Aim 1, we will use ?repair fingerprinting? to determine whether DNA double strand breaks are formed or repaired differently in astrocytes and neurons, and what pathways are involved. Repair fingerprinting is an integrated three-arm approach to identify the landscape of DNA repair and extract which pathways and machinery are responsible for the DSBR in brain cells.
In Aim 2, we will determine whether cryptic DNA double strand breaks are the primary driver of neuronal death in HdhQ(150/150) mice in vivo.
We find that DSBs may be are killing brain cells in Huntington disease and that differential repair in astrocytes and neurons account for their sensitive to death. We will apply ?Repair Fingerprinting? as a powerful and integrated approach to link DNA repair to toxicity.
|Polyzos, Aris A; Wood, Nigel I; Williams, Paul et al. (2018) XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent. PLoS One 13:e0194580|
|Polyzos, Aris A; McMurray, Cynthia T (2017) The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington's disease. Mech Ageing Dev 161:181-197|
|Polyzos, Aris A; McMurray, Cynthia T (2017) Close encounters: Moving along bumps, breaks, and bubbles on expanded trinucleotide tracts. DNA Repair (Amst) 56:144-155|
|Lai, Yanhao; Budworth, Helen; Beaver, Jill M et al. (2016) Crosstalk between MSH2-MSH3 and pol? promotes trinucleotide repeat expansion during base excision repair. Nat Commun 7:12465|
|Budworth, Helen; McMurray, Cynthia T (2016) Problems and solutions for the analysis of somatic CAG repeat expansion and their relationship to Huntington's disease toxicity. Rare Dis 4:e1131885|
|Polyzos, Aris; Holt, Amy; Brown, Christopher et al. (2016) Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes. Hum Mol Genet 25:1792-802|
|Budworth, Helen; Harris, Faye R; Williams, Paul et al. (2015) Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease. PLoS Genet 11:e1005267|
|McMurray, Cynthia T; Vijg, Jan (2014) Editorial overview: Molecular and genetic bases of disease: the double life of DNA. Curr Opin Genet Dev 26:v-vii|
|Lee, Do-Yup; McMurray, Cynthia T (2014) Trinucleotide expansion in disease: why is there a length threshold? Curr Opin Genet Dev 26:131-40|
|Platt, Virginia; Lee, Do Yup; Canaria, Christie A et al. (2013) Towards understanding region-specificity of triplet repeat diseases: coupled immunohistology and mass spectrometry imaging. Methods Mol Biol 1010:213-30|
Showing the most recent 10 out of 19 publications