Clévio Nóbrega

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common dominantly- inherited disorder, originally described in people of Portuguese descent, caused by an expansion of a (CAG)n tract in the coding region of the gene MJD1. The abnormal over-repetition of the CAG-trinucleotide is translated into an expanded polyglutamine tract within ataxin-3, resulting in severe clinical features and leading to death. There is no therapy for this fatal disease.

Ataxin-2 is a protein whose function has been linked to translational regulation. There is evidence that ataxin-2 interacts with poly-a-binding protein (PABPC1, which is required for poly(A) shortening and translation initiation) in polyribosomes, thus reducing protein translation. Recent studies suggested a role of ATAX2 in other neurodegenerative disorders such as SCA1 or Amyotrophic lateral sclerosis. In MJD several evidences also point to a potential link with ataxin-2, as this protein is detected in mutant ataxin-3 nuclear inclusions. Moreover, our results points to a downregulation of ataxin-2 levels (both mRNA and protein) in MJD. Nevertheless, it is not known how these two proteins interact and lead to disease pathology.

In this project we hypothesize that the trapping of ataxin-2 in MJD, reduces soluble ataxin-2 levels freeing PABPC1 to an overactive protein translation, particularly of ataxin-3, which may contribute decisively to the pathology. This study will contribute to sort out the pathogenic mechanism of MJD, to validate the therapeutic target – Ataxin-2 mediated translational inhibition – and hopefully for the development of a therapy for MJD.