Role of TFEB in Huntington's Disease

Simple Summary Huntington's disease is an inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein, which leads to its accumulation and neuronal death. There are several therapeutic strategies aimed at reducing the levels of mutant huntingtin, one of which is to activate cellular degradation systems such as autophagy. The transcription factor TFEB is the key regulator of gene expression in the autophagy-lysosomal pathway. In this review, we describe how the modulation of TFEB expression in HD models affect the levels of mutant huntingtin. Further studies are needed to assess whether targeting TFEB or stimulating autophagy could be a suitable therapeutic strategy to reduce the HD phenotype.Abstract Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy-lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models.