Molecular mechanisms underlying Spinocerebellar Ataxia 17 (SCA17) pathogenesis

Abstract

Spinocerebellar ataxia 17 (SCA17) belongs to the family of 9 genetically inherited, late-onset neurodegenerative diseases, which are caused by polyglutamine (polyQ) expansion in different proteins. In SCA17, the polyQ expansion occurs in the TATA box binding protein (TBP), which functions as a general transcription factor. Patients with SCA17 suffer from a broad array of motor and non-motor defects, and their life expectancy is normally within 20 y after the initial appearance of symptoms. Currently there is no effective treatment, but remarkable efforts have been devoted to tackle this devastating disorder. In this review, we will summarize our current knowledge about the molecular mechanisms underlying the pathogenesis of SCA17, with a primary focus on transcriptional dysregulations. We believe that impaired transcriptional activities caused by mutant TBP with polyQ expansion is a major form of toxicity contributing to SCA17 pathogenesis, and rectifying the altered level of downstream transcripts represents a promising therapeutic approach for the treatment of SCA17.

Keywords: SCA17; TBP; polyglutamine; transcription.

Figure 1.

Transcriptional dysregulations in SCA17 A brief summary of our current understanding about the transcription factors and their mediated cellular processes impaired by mutant TBP. Mutant TBP affects the activities of these transcription factors through 2 distinct mechanisms. One is gain of function, which means mutant TBP showed enhanced interactions with the transcription factors, thereby sequestering them from their functional locations. The other one is loss of function, which means while wild type TBP is an essential component of the transcriptional complexes, mutant TBP fails to carry out the same functions as wild type TBP.