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

Abstract

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.

Diffusion imaging in Huntington’s disease: comprehensive review

“… 5 Inactivation of mHTT within oligodendrocytes prevents myelin deficiencies and ameliorates behavioural phenotypes in mouse models of HD, possibly due to improved cholesterol metabolism and increased transcription of myelin regulator factor. 6 However, most experimental evidence about histological abnormalities in HD is based on mouse models. 4 Therefore, investigating WM microstructure in neurodegeneration in vivo through neuroimaging is critical to the understanding of neurological diseases such as HD.…”

Oligodendroglial Heterogeneity in Neuropsychiatric Disease

“…Additional evidence of early WM pathology and oligodendroglial dysfunction onset prior to overt neuronal death has been shown in several mouse models of HD [ 25 , 26 ], and different transgenic animal models have been used to investigate the effect of the expanded mutant HTT ( mHTT ) expression more specifically in oligodendroglial populations. In one example, Huang et al [ 27 ] expressed a HTT fragment under the oligodendrocyte promoter PLP, and compared the effects of a fragment with expanded CAG repeat length to a healthy HTT fragment.…”

“…These animals also showed decreased expression of mature oligodendrocyte markers such as myelin basic protein (MBP) and myelin-oligodendrocyte glycoprotein (MOG), as well as thinning of the myelin sheaths and shortened oligodendrocyte processes. Ferrari-Bardile et al [ 26 ] applied the reverse approach, of lowering the expression of mHTT under the glial progenitor promoter NG2, thus reducing levels of mHTT only in oligodendroglia, using a different transgenic mouse model of HD expressing mHTT globally. This was sufficient to rescue myelin deficits in the HD mouse, as well as improving performance in behavioural tests.…”

Modulating glial genes involved in synaptic function mitigates pathogenesis and behavioral deficits in aDrosophilamodel of Huntington’s Disease

“…There is, in fact, emerging evidence that various glial subtypes affect outcomes in HD. The accumulation of mHTT in astrocytes and oligodendrocytes hinders their development and function and contributes to disease pathophysiology (Benraiss et al, 2016; Ferrari Bardile et al, 2019; Osipovitch et al, 2019; Wood et al, 2018). Conversely, healthy glia can improve the disease phenotype in HD mice (Benraiss et al, 2016).…”