Affiliations: [a] Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), Singapore
Departments of Medicine and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
British Columbia Children’s Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Correspondence to: Mahmoud A. Pouladi, Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), Singapore 138648. E-mail: [email protected].
Abstract: Background:The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective:We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods:Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results:We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion:Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities.
Keywords: Huntington’s disease, spinal cord, white matter, oligodendroglia, myelin sheath