Htt-KO Mouse

Htt, short for huntingtin, is encoded by the HTT gene. An abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to Huntington's disease (HD), a devastating neurodegenerative disorder [1]. HTT is ubiquitous at both tissue and subcellular levels, interacting with many partners, yet its cellular function has long been elusive [1].

HD is caused by a CAG repeat expansion in exon 1 of the HTT gene, which is translated into a polyglutamine stretch in the huntingtin protein [2]. In YAC128 mice transgenic for human HTT with an expanded CAG repeat, an exon 1 only transcript (HTT1a) was detected, which is translated to produce the highly aggregation-prone and pathogenic exon 1 HTT protein, and its levels correlated with HTT aggregation [2]. In HD knock-in mice expressing full-length mutant HTT, the numbers of astrocytes and oligodendrocytes were not significantly altered, but myelin protein expression and myelin thickness of axons were reduced at 3 months of age, suggesting cytoplasmic mutant HTT mediates myelination defects in early disease stages without impacting glial cell differentiation and maturation [3].

In conclusion, the study of Htt through mouse models like YAC128 and HD knock-in mice has revealed that mutant Htt is closely associated with the pathogenesis of Huntington's disease, especially in aspects such as protein aggregation and myelination defects. Understanding the function of Htt and the impact of its mutation is crucial for developing therapies for HD.

References:

1. Saudou, Frédéric, Humbert, Sandrine. . The Biology of Huntingtin. In Neuron, 89, 910-26. doi:10.1016/j.neuron.2016.02.003. https://pubmed.ncbi.nlm.nih.gov/26938440/

2. Fienko, Sandra, Landles, Christian, Sathasivam, Kirupa, Kordasiewicz, Holly B, Bates, Gillian P. . Alternative processing of human HTT mRNA with implications for Huntington's disease therapeutics. In Brain : a journal of neurology, 145, 4409-4424. doi:10.1093/brain/awac241. https://pubmed.ncbi.nlm.nih.gov/35793238/

3. Yang, Sitong, Ma, Jingjing, Zhang, Han, Li, Xiao-Jiang, Guo, Xiangyu. 2023. Mutant HTT does not affect glial development but impairs myelination in the early disease stage. In Frontiers in neuroscience, 17, 1238306. doi:10.3389/fnins.2023.1238306. https://pubmed.ncbi.nlm.nih.gov/37539389/