TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs

Abstract

A BS TRACT: Background: Huntington's disease (HD) is a neurodegenerative disease caused by CAG-repeat expansions (>36) in exon 1 of HTT, which dysregulates multiple cellular machineries. Translin-associated protein X (TRAX) is a scaffold protein with diverse functions, including suppressing the microRNA (miRNA)mediated silencing by degrading pre-miRNA. To date, the role of TRAX in neurodegenerative diseases remains unknown. Objectives: We delineated the role of TRAX upregulation during HD progression. Methods: Expression of TRAX in the brains of humans and three mouse models with HD were analyzed by immunohistochemistry staining, western blot, and quantitative reverse transcription-polymerase chain reaction. Adeno-associated viruses harboring TRAX short hairpin RNA were intrastriatally injected into HD mice to downregulate TRAX. HD-like symptoms were analyzed by behavioral and biochemical assessments. The miRNAsequencing and RNA-sequencing analyses were used to identify the TRAX-regulated miRNA-messenger RNA (mRNA) axis during HD progression. The identified gene targets were validated biochemically in mouse and human striatal cells. Results: We discovered that TRAX was upregulated in the brains of HD patients and three HD mouse models. Downregulation of TRAX enhanced 83 miRNAs (including miR-330-3p, miR-496a-3p) and subsequently changed the corresponding mRNA networks critical for HD pathogenesis (eg, DARPP-32 and brain-derived neurotrophic factor). Disruption of the TRAX-mediated miRNA-mRNA axis accelerated the progression of HD-like symptoms, including the degeneration of motor function, accumulation of mHTT aggregates, and shortened neurite outgrowth. Conclusions: We demonstrated that TRAX upregulation is authentic and protective in HD. Our study provides a novel layer of regulation for HD pathogenesis and may lead to the development of new therapeutic strategies for HD.

The Impact of Dysregulated microRNA Biogenesis Machinery and microRNA Sorting on Neurodegenerative Diseases

“…Some of these TRAX-sensitive mRNAs, including protein phosphatase 1 regulatory subunit 1B ( PPP1R1B , the gene encoding dopamine-and cAMP-regulated neuronal phosphoprotein; DARPP-32) and brain-derived neurotrophic factor ( BDNF ), were shown to play key roles in HD pathogenesis. Furthermore, downregulation of TRAX in the striatum of HD mice accelerated the motor symptoms of HD, increased the size of mHTT aggregates, and decreased neurite outgrowth, suggesting that TRAX upregulation is protective in HD [ 100 ].…”