Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington's disease

Abstract

White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD.

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

“…Numerous studies have also reported extensive alterations in white matter tract (WMT) architecture in HD cases and animal models (Bohanna et al, 2011; Jin et al, 2015; Paulsen et al, 2006; Phillips et al, 2014). Thus, we next examined the status of myelination of cortical deep layers at 12-months of age.…”

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

“…Impaired myelination has been reported in HD patients (Bartzokis et al, 2007) and mouse models (Xiang et al, 2011; Jin et al, 2015). The molecular mechanisms underlying this white matter abnormality are largely unknown, although PGC-1α deficiency (Xiang et al, 2011) and altered proliferation of oligodendrocyte precursor cell (Jin et al, 2015) could be contributing factors.…”

“…The molecular mechanisms underlying this white matter abnormality are largely unknown, although PGC-1α deficiency (Xiang et al, 2011) and altered proliferation of oligodendrocyte precursor cell (Jin et al, 2015) could be contributing factors. Interestingly, our study revealed that p75 NTR - and sortilin-immunoreactivities are both significantly elevated in a subset of immature striatal oligodendrocytes in aged zQ175 HD mice, and this correlates with myelination defect in the HD striatum.…”

Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

“…HdhQ150 mice displayed some HD symptoms that seem more severe in homozygous mice [33,39,40]. Recently, heterozygous hdhQ250 mice have been generated from hdhQ150 by selective breeding and shown more severe neurological symptoms than heterozygous hdhQ150 mice [41]. Hdh4/Q80 and Hdh6/Q72 mice have also been obtained by replacement of short CAG repeat with 72 or 80 CAG repeat expansions in htt murine gene context.…”