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

Roy Tang Yi Teo,Michael R Hayden,Liang Juin Tan,Yihui Huang,Libo Yu-Taeger,Xin Hong,Huu P Nguyen,Arianna Novati,Carsten Calaminus,Kai-Hsiang Chuang,Yuanyun Xie,Reshmi Rajendran,Olaf Riess,Xuan Vinh To,Ling Guo,Mahmoud A Pouladi

doi:10.1093/hmg/ddw122

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.

Highlights

Huntington disease (HD) is an autosomal dominant hereditary disorder characterized by loss of motor control, cognitive deficits and psychiatric disturbances [1]
Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural White matter (WM) abnormalities occur from an early age in YAC128 mice
Voxel-wise analysis indicated that fractional anisotropy (FA) values were significantly lower in the WM-rich brain regions of YAC128 mice compared with wildtype (WT) mice, including in the anterior commissure (AC), corpus callosum (CC), internal capsule and external capsule (EC) from 1.5 months of age, and in the cingulum (CG) and cerebral peduncle from 3 months of age (Fig. 1A and B; Supplementary Material, Table S1)

Summary

Introduction

Huntington disease (HD) is an autosomal dominant hereditary disorder characterized by loss of motor control, cognitive deficits and psychiatric disturbances [1]. In addition to structural MRI, magnetic resonance diffusion tensor imaging (MRDTI), which has been widely used to examine the integrity of neuronal tract connectivity, suggests the presence of microstructural abnormalities in myelinated tracts in patients with HD and in pre-symptomatic gene carriers [12,13,14]. While these studies support the occurrence of WM abnormalities as an early event in HD, they do not preclude the possibility that these changes are secondary to neuronal loss. The nature of these WM abnormalities at a molecular and microstructural level remains poorly defined

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