title: 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.
authors.affiliation: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore 138648, Singapore.
authors.forename: Roy Tang Yi
authors.initials: RT
authors.lastname: Teo
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.|Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Libo
authors.initials: L
authors.lastname: Yu-Taeger
authors.affiliation: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore 138648, Singapore.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore 138648, Singapore.
authors.forename: Liang Juin
authors.initials: LJ
authors.lastname: Tan
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Yuanyun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Xuan Vinh
authors.initials: XV
authors.lastname: To
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Reshmi
authors.initials: R
authors.lastname: Rajendran
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.|Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Arianna
authors.initials: A
authors.lastname: Novati
authors.affiliation: Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Calaminus
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.|Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore 138648, Singapore.|Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138648, Singapore.
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore 138648, Singapore pouladi@tlgm.a-star.edu.sg map@pouladilab.org.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
mesh_terms: D000818:Animals; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000378:metabolism; D003337:Corpus Callosum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D056324:Diffusion Tensor Imaging / Q000379:methods; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D051381:Rats; D066127:White Matter / Q000503:physiopathology*
chemical_list: D009419:Nerve Tissue Proteins