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TRMT2A DOSAGE MODULATES MOTOR DECLINE AND CEREBELLAR NEURODEGENERATION IN A MJD/SCA3 MOUSE MODEL
Tiago Gomesand 5 co-authors
ABC-RI, Algarve Biomedical Center Research Institute, Universidade do Algarve
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-261
Presentation
Date TBA
Board: PS04-08PM-261
Event Information
Poster Board
PS04-08PM-261
Poster
View posterAbstract
Machado-Joseph disease (MJD), or Spinocerebellar ataxia type 3 (SCA3), is a polyglutamine disorder caused by an abnormal trinucleotide (CAG) expansion in the ATXN3 gene, leading to the production of a mutant ATAXIN-3 protein. This mutation results in neurodegeneration and neuronal loss in specific brain regions, causing severe motor and functional impairments, negatively impacting their quality of life. Currently, there are no therapies to halt or slow disease progression, highlighting the need to identify novel disease-modifying targets. Previous studies have demonstrated that the loss of tRNA methyltransferase 2 homolog A (TRMT2A) reduces polyglutamine toxicity and aggregation in MJD/SCA3 fibroblasts and Drosophila models. Despite this, the therapeutic impact of Trmt2a knockout in an MJD/SCA3 mammal model was not addressed. Therefore, the present work aims to investigate in detail the impact of Trmt2a knockout in a transgenic MJD/SCA3 mouse model. MJD/SCA3 mice with the genotypes Trmt2a+/+, Trmt2a+/-, and Trmt2a-/- underwent motor behavioral tests every 4 weeks of age for 12 weeks. In comparison to the control groups, MJD/SCA3 Trmt2a-/- mice exhibited an improvement of motor performance, and an increase in the number of Purkinje cells and in the thickness of the cerebellar molecular layer, suggesting neuroprotection. Transcriptomic analyses of animal cerebella shed light on cellular pathways relevant to MJD/SCA3 pathogenesis impacted by the absence of TRMT2A protein, namely on neuronal signaling and homeostasis pathways. These findings suggest that TRMT2A holds promise as a potent therapeutic target, potentially paving the way for novel disease-modifying treatments for MJD/SCA3, both based on pharmacological and advanced medicines.
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