Objective: Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) is a neurodegenerative disorder caused by a CAG expansion in the MJD1 gene leading to a polyglutamine expansion in the encoded ataxin-3 protein. In controls, ataxin-3 is predominantly located in the cytoplasm but forms protein aggregates in the nucleus of neurons in SCA3 patients. The questions remains why and how ataxin-3 translocates to the nucleus during the pathogenesis of SCA3.

Background: We recently demonstrated in vivo that the toxicity of expanded ataxin-3 is linked to its intracellular localization: Targeting ataxin-3 to the nucleus gave rise to a strong phenotype with a high number of protein aggregates while purely cytoplasmic ataxin 3 was not able to induce a phenotype. In addition, we identified and characterized intracellular transport signals (two nuclear export signals and one nuclear localization signal) within the coding sequence of ataxin-3.

Methods: In order to identify transport proteins involved in the nucleocytoplasmic shuttling of ataxin-3, we screened a library of transport proteins by overexpressing and/or downregulating transport proteins. As we observed in our mouse model that nuclear export of ataxin-3 correlates with the formation of aggregates, we used its aggregation as readout for this screen.

Results: We identified a transport protein which modifies both the formation of aggregates and the intracellular localization of ataxin 3. While the overexpression of this protein moved ataxin-3 into the nucleus, its downregulation kept it out of the nucleus. We replicated this correlation in vivo in drosophila and observed in addition to this again a clear link between the intracellular localization of ataxin-3 and its toxicity i.e. its ability of induce neurodegeneration and a behavioral phenotype. Likewise we even confirmed in a mouse model of SCA3 the importance of the identified transport protein as its knockout largely prevented ataxin-3 from aggregating and alleviated behavioral and movement deficits.

Conclusions: Our results demonstrate that transport proteins are involved in the intracellular localization of ataxin-3 and the neurodegenerative processes in SCA3. Understanding the mechanisms behind the intracellular transport of ataxin-3 could give us clues into the pathogenic functions of expanded ataxin-3 and ways to mediate the progression of neuronal degeneration in SCA3.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-nucleocytoplasmic-transport-of-ataxin-3-as-pathogenic-mechanism-in-spinocerebellar-ataxia-type-3/