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Impaired Remyelination in a Mouse Model of Huntington Disease

  • Roy Tang Yi Teo
  • Costanza Ferrari Bardile
  • Yi Lin Tay
  • Nur Amirah Binte Mohammad Yusof
  • Charbel A. Kreidy
  • Liang Juin Tan
  • Mahmoud A. PouladiEmail author
Article

Abstract

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.

Keywords

Huntington disease White matter Myelination Oligodendrocytes Plasticity 

Notes

Acknowledgements

We thank Maria Ericsson (Electron Microscopy Facility, Harvard Medical School) for electron microscopy and the SBIC-Nikon Imaging Centre (A*STAR, Biopolis) for confocal imaging services.

Authors’ Contribution

R.T.Y.T. and M.A.P. conceived and planned the study. R.T.Y.T., C.F.B., N.A.B.M.Y., C.A.K., and L.J.T. performed experiments. R.T.Y.T. and M.A.P. analyzed data. Y.L.T. provided intellectual input. R.T.Y.T., Y.L.T., and M.A.P. wrote and revised the manuscript.

Funding information

C.F.B. is supported by a Singapore International Graduate Award (SINGA) from the Agency for Science, Technology and Research (A*STAR). The work was supported by grants from the Agency for Science, Technology and Research (A*STAR) and the National University of Singapore to M.A.P.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1579_MOESM1_ESM.docx (4.8 mb)
Supplementary Figure 1 (DOCX 4917 kb)

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Authors and Affiliations

  1. 1.Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR)SingaporeSingapore
  2. 2.Department of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Department of PhysiologyNational University of SingaporeSingaporeSingapore

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