Abstract
Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington’s disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain development recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.
Highlights
Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the huntingtin gene (HTT), which encodes an expanded polyglutamine stretch in the huntingtin protein (HTT)
To determine the molecular basis of abnormal striatal volume development in male zQ175 mice, we examined the markers of myelin development, including the levels of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG)
The motivation for this study was two-fold. It was prompted by a series of cellular and molecular findings that has established brain developmental abnormalities contribute to HD pathogenesis (Arteaga-Bracho et al 2016; Nguyen et al 2013a; Nguyen et al 2013b; Molero et al 2016; Mehler et al 2019)
Summary
Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the huntingtin gene (HTT), which encodes an expanded polyglutamine stretch in the huntingtin protein (HTT). Cumulative cellular and molecular studies have demonstrated that brain developmental abnormalities may be a substrate for impaired brain function and later neurodegeneration in HD (Mehler and Gokhan 2000; Reiner et al 2003; Cattaneo et al 2005; Godin et al 2010; Molina-Calavita et al 2014; Conforti et al 2018; Wiatr et al 2018; Barnat et al 2020). The previous study indicated that mutant HTT (mHTT)-associated developmental impairments in neurogenesis may contribute to regional and cellular vulnerabilities to late selective neurodegeneration (Nguyen et al 2013a; Nguyen et al 2013b; Molero et al 2016). Transcriptomic studies have indicated that genes with key developmental and neural functions are preferentially impacted in the brain samples carrying mutant HTT (Jin et al 2012; Achour et al 2015; Labadorf et al 2015)
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