Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease

• Main Authors: Bardile, Costanza Ferrari, Garcia-Miralles, Marta, Caron, Nicholas S., Rayan, Nirmala Arul, Langley, Sarah Raye, Harmston, Nathan, Rondelli, Ana Maria, Teo, Roy Tang Yi, Waltl, Sabine, Anderson, Lisa M., Bae, Han-Gyu, Jung, Sangyong, Williams, Anna, Prabhakar, Shyam, Petretto, Enrico, Hayden, Michael R., Pouladi, Mahmoud A.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2020
• Subjects: Science::Medicine; Huntington Disease; White Matter
• Online Access: https://hdl.handle.net/10356/144753
• Institution: Nanyang Technological University

White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white matter pathology is simply a secondary outcome of the progressive neuronal loss that manifests with advancing disease. Using a mouse model of HD, here we show that white matter and myelination abnormalities are an early disease feature appearing before the manifestation of any behavioral abnormalities or neuronal loss. We further show that selective inactivation of mutant huntingtin (mHTT) in the NG2+ oligodendrocyte progenitor cell population prevented myelin abnormalities and certain behavioral deficits in HD mice. Strikingly, the improvements in behavioral outcomes were seen despite the continued expression of mHTT in nonoligodendroglial cells including neurons, astrocytes, and microglia. Using RNA-seq and ChIP-seq analyses, we implicate a pathogenic mechanism that involves enhancement of polycomb repressive complex 2 (PRC2) activity by mHTT in the intrinsic oligodendroglial dysfunction and myelination deficits observed in HD. Our findings challenge the long-held dogma regarding the etiology of white matter pathology in HD and highlight the contribution of epigenetic mechanisms to the observed intrinsic oligodendroglial dysfunction. Our results further suggest that ameliorating white matter pathology and oligodendroglial dysfunction may be beneficial for HD.