Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease

Abstract

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…Given that improvements in behavioral outcomes were mainly observed in animals that received early pridopidine treatment, we decided to evaluate pridopidine's efficacy on HD-related neuropathology in this particular cohort. Striatal atrophy and white matter abnormalities are neuropathological features observed in patients with HD that have also been described in YAC128 HD mice (22,28,29). To assess whether pridopidine could also have therapeutic effects on HD-related neuropathology, we measured striatal and corpus callosum (CC) volume by structural MRI.…”

“…Structural T2-TSE images were cropped and corrected for signal inhomogeneity using MIPAV (http://mipav.cit.nih.gov/) N3 inhomogeneity correction (69). The images were then nonlinearly registered using FSL's (http://fsl.fmrib.ox.ac.uk/fsl) FNIRT (72) to an in-house created template from registered brain images of 9-month-old YAC128 and WT mice from a previous study (29).…”

Gradual Phenotype Development in Huntington Disease Transgenic Minipig Model at 24 Months of Age

“…Furthermore, we detected demyelination, which occurs prior to neuronal loss in mice models of HD (YAC128 and BACHD) [46], in TgHD minipigs at 24 months. This indicates an ongoing premanifest stage in TgHD mini­pigs at this age.…”

Manipulation of microbiota reveals altered myelination and white matter plasticity in a model of Huntington disease

“…Previous work in our laboratory has also explored the molecular and ultrastructural features of WM abnormalities in HD mouse and rat models (Garcia-Miralles et al, 2016;Teo et al, 2016). For example, diffusion tensor imaging revealed WM microstructural abnormalities prior to neuronal loss in the CC of the YAC128 mouse model and the BACHD rat model (Teo et al, 2016). In addition, thinner myelin sheaths and lower levels of myelin-related gene transcripts were seen in these animals compared to wild-type (WT) controls (Teo et al, 2016).…”

“…White matter alterations were found in the corpus callosum (CC) and prefrontal cortex (PFC) of presymptomatic and symptomatic HD gene carriers (Ross and Tabrizi, 2011;Matsui et al, 2014;Matsui et al, 2015;Bourbon-Teles et al, 2017). Previous work in our laboratory has also explored the molecular and ultrastructural features of WM abnormalities in HD mouse and rat models (Garcia-Miralles et al, 2016;Teo et al, 2016). For example, diffusion tensor imaging revealed WM microstructural abnormalities prior to neuronal loss in the CC of the YAC128 mouse model and the BACHD rat model (Teo et al, 2016).…”