A new study from Academia Sinica revealed a novel neuroprotective mechanism against Huntington’s disease via the TRAX-mediated alteration of a subset of miRNA. This study was published in “Movement Disorders” in August, 2022.
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene that encodes mutant Huntingtin protein (mHTT). The accumulation of mHTT aggregates impairs multiple cellular machineries and causes neurodegeneration. During HD progression, the level of the Translin-associated protein X (TRAX, a scaffold protein that mediates miRNA degradation) was markedly enhanced in the brain of patients and mice with HD. Such TRAX upregulation is protective in HD, because genetic downregulation of TRAX in the brain of HD mice altered the miRNA-mRNA network and accelerated disease progression as determined by motor coordination and mHTT aggregation. In total, the suppression of TRAX elevated 83 miRNAs (including miR-330-3p, miR-496a-3p) and consequently afflicted the corresponding mRNA networks (e.g., DARPP-32 and BDNF) essential for HD pathogenesis. The importance of TRAX- mediated miR-330-3p- DARPP-32 axis was further validated in both mouse striatal neurons and human striatal neurons differentiated from iPSC. These findings suggest that TRAX is a new drug target for HD and may pave the way for the development of novel therapeutic strategies for HD.
This study was accomplished by a team led by Dr. Yijuang Chern (Academia Sinica) and funded by Academia Sinica. The first author (Ms. Yu-Ting Weng) is a Ph. D. student of Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taiwan.
The article entitled “TRAX Provides Neuroprotection for Huntington’s Disease Via Modulating a Novel Subset of MicroRNAs”, can be read online at: