Neuron
Volume 85, Issue 6, 18 March 2015, Pages 1212-1226
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Article
Mutant Huntingtin Downregulates Myelin Regulatory Factor-Mediated Myelin Gene Expression and Affects Mature Oligodendrocytes

https://doi.org/10.1016/j.neuron.2015.02.026Get rights and content
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Highlights

  • Mutant huntingtin is expressed in oligodendrocytes and affects their processes

  • Mutant huntingtin causes age-dependent demyelination and symptoms in HD mice

  • Mutant huntingtin reduces myelin gene expression

  • Mutant huntingtin binds MYRF to affect its transcriptional activity

Summary

Growing evidence indicates that non-neuronal mutant huntingtin toxicity plays an important role in Huntington’s disease (HD); however, whether and how mutant huntingtin affects oligodendrocytes, which are vitally important for neural function and axonal integrity, remains unclear. We first verified the presence of mutant huntingtin in oligodendrocytes in HD140Q knockin mice. We then established transgenic mice (PLP-150Q) that selectively express mutant huntingtin in oligodendrocytes. PLP-150Q mice show progressive neurological symptoms and early death, as well as age-dependent demyelination and reduced expression of myelin genes that are downstream of myelin regulatory factor (MYRF or MRF), a transcriptional regulator that specifically activates and maintains the expression of myelin genes in mature oligodendrocytes. Consistently, mutant huntingtin binds abnormally to MYRF and affects its transcription activity. Our findings suggest that dysfunction of mature oligodendrocytes is involved in HD pathogenesis and may also make a good therapeutic target.

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