Impaired Remyelination in a Mouse Model of Huntington Disease.

White matter (WM) abnormalities are a well-established feature of Huntington disease (HD), although their nature is not fully understood. Here, we asked whether remyelination as a measure of WM plasticity is impaired in a model of HD. Using the cuprizone assay, we examined demyelination and remyelination responses in YAC128 HD mice. Treatment with 0.2% cuprizone (CPZ) for 6 weeks resulted in significant reduction in mature (GSTπ-positive) oligodendrocyte counts and FluoroMyelin staining in the corpus callosum, leading to similar demyelination states in YAC128 and wild-type (WT) mice. Six weeks following cessation of CPZ, we observed robust remyelination in WT mice as indicated by an increase in mature oligodendrocyte counts and FluoroMyelin staining. In contrast, YAC128 mice exhibited an impaired remyelination response. The increase in mature oligodendrocyte counts in YAC128 HD mice following CPZ cessation was lower than that of WT. Furthermore, there was no increase in FluoroMyelin staining compared to the demyelinated state in YAC128 mice. We confirmed these findings using electron microscopy where the CPZ-induced reduction in myelinated axons was reversed following CPZ cessation in WT but not YAC128 mice. Our findings demonstrate that remyelination is impaired in YAC128 mice and suggest that WM plasticity may be compromised in HD.

Unbiased Profiling of Isogenic Huntington Disease hPSC-Derived CNS and Peripheral Cells Reveals Strong Cell-Type Specificity of CAG Length Effects.

In Huntington disease (HD), the analysis of tissue-specific CAG repeat length effects has been challenging, given the difficulty in obtaining relevant patient tissues with a broad range of CAG repeat lengths. We used genome editing to generate an allelic panel of isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying CAG repeat lengths in the first exon of HTT. Functional analyses in differentiated neural cells revealed CAG repeat length-related abnormalities in mitochondrial respiration and oxidative stress and enhanced susceptibility to DNA damage. To explore tissue-specific effects in HD, we differentiated the IsoHD panel into neural progenitor cells, neurons, hepatocytes, and muscle cells. Transcriptomic and proteomic analyses of the resultant cell types identified CAG repeat length-dependent and cell-type-specific molecular phenotypes. We anticipate that the IsoHD panel and transcriptomic and proteomic data will serve as a versatile, open-access platform to dissect the molecular factors contributing to HD pathogenesis.