XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent

Polyzos, Aris A.; Wood, Nigel I.; Williams, Paul; Wipf, Peter; Morton, A. Jennifer; McMurray, Cynthia T.

doi:10.1371/journal.pone.0194580

Title: XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent

Journal Article · 08 April 2018 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0194580 · OSTI ID:1627858

^[1]; Wood, Nigel I. ^[2]; Williams, Paul ^[3]; Wipf, Peter ^[4]; Morton, A. Jennifer ^[2];

^[3]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division; DOE/OSTI
Univ. of Cambridge (United Kingdom). Dept. of Physiology, Development, and Neuroscience
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
Univ. of Pittsburgh, PA (United States). Dept. of Chemistry

We have reported that the radical scavenger XJB-5-131 attenuates or reverses progression of the disease phenotype in the HdhQ(150/150) mouse, a slow onset model of HD. Here, we tested whether XJB-5-131 has beneficial effects in R6/2 mice, a severe early onset model of HD. We found that XJB-5-131 has beneficial effects in R6/2 mice, by delaying features of the motor and histological phenotype. The impact was sex-dependent, with a stronger effect in male mice. XJB-5-131 treatment improved some locomotor deficits in female R6/2 mice, but the effects were, in general, greater in male mice. Chronic treatment of male R6/2 mice with XJB-5-1-131 reduced weight loss, and improved the motor and temperature regulation deficits, especially in male mice. Treatment with XJB-5-131 had no effect on the lifespan of R6/2 mice. Nevertheless, it significantly slowed somatic expansion at 90 days, and reduced the density of inclusions. Our data show that while treatment with XJB-5-131 had complex effects on the phenotype of R6/2 mice, it produced a number of significant improvements in this severe model of HD.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1627858

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 4 Vol. 13; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations Kovtun, I. V.; Thornhill, A. R.; McMurray, C. T. Human Molecular Genetics, Vol. 13, Issue 24 https://doi.org/10.1093/hmg/ddh325	journal	October 2004
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Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease Van Raamsdonk, Jeremy M.; Pearson, Jacqueline; Rogers, Daniel A. Human Molecular Genetics, Vol. 14, Issue 10 https://doi.org/10.1093/hmg/ddi147	journal	April 2005
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Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes Polyzos, Aris; Holt, Amy; Brown, Christopher Human Molecular Genetics, Vol. 25, Issue 9 https://doi.org/10.1093/hmg/ddw051	journal	February 2016
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Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats Javadov, Sabzali; Jang, Sehwan; Rodriguez-Reyes, Natividad Oncotarget, Vol. 6, Issue 37 https://doi.org/10.18632/oncotarget.5783	journal	September 2015
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Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington’s Disease Skillings, Elizabeth A.; Morton, A. Jennifer Journal of Huntington's Disease, Vol. 5, Issue 1 https://doi.org/10.3233/JHD-160189	journal	March 2016

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Chronic Exposure to Cadmium and Antioxidants Does Not Affect the Dynamics of Expanded CAG•CTG Trinucleotide Repeats in a Mouse Cell Culture System of Unstable DNA Gomes-Pereira, Mário; Monckton, Darren G. Frontiers in Cellular Neuroscience, Vol. 14 https://doi.org/10.3389/fncel.2020.606331	journal	February 2021
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Impaired Redox Signaling in Huntington’s Disease: Therapeutic Implications Paul, Bindu D.; Snyder, Solomon H. Frontiers in Molecular Neuroscience, Vol. 12 https://doi.org/10.3389/fnmol.2019.00068	journal	March 2019

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