Objective: Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) is an autosomal-dominantly inherited neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the encoded ataxin-3 protein. There is still no treatment available for this disease. We therefore aim to develop a novel treatment strategy for SCA3/MJD.

Background: Characteristic for SCA3 are the so called neuronal intranuclear inclusion bodies (NII).  As ataxin-3 is predominantly located in the cytoplasm, the formation of protein aggregates in the nucleus require a nucleocytoplasmic shuttling of ataxin-3. We already demonstrated in vivo that the toxicity of expanded ataxin-3 is linked to its intracellular localization: Only nuclear ataxin-3 gave rise to a phenotype while purely cytoplasmic ataxin-3, however, even with a highly expanded polyglutamine repeat, remained harmless. We then dissected the nucleocytoplasmic transport mechanisms of ataxin-3 and identified a transport protein with critical importance for the nuclear import of ataxin-3.

Methods:  As pathologically ataxin-3 remains harmless as long as it is kept in the cytoplasm, we further anticipated the intracellular localization of ataxin-3 as a target for a possible therapeutical intervention. For this reason, we generated an assay allowing us to easily monitor the intracellular localization of normal or expanded ataxin-3 and used our assay to screen a library of FDA-approved compounds. 

Results: We identified compounds impacting the nuclear translocation of ataxin-3 and validated them in vitro and in vivo. As the compounds we identified are already FDA-approved and on the market, they could be transferred to the clinics comparatively fast. We believe that our results will improve the understanding of pathological mechanisms influencing the progression of the disease and are an important contribution towards a treatment of SCA3.

Conclusions: Our results demonstrate that nuclear transport processes are critical for the pathophysiology of SCA3/MJD and that it is possible to impact and thereby alleviate symptoms induced by expanded ataxin-3 using specific compounds. We believe that our results will improve the understanding of mechanisms influencing the pathogenesis of SCA3/MJD and are an important contribution towards a treatment of this disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-the-intracellular-localization-of-ataxin-3-as-novel-treatment-strategy-for-spinocerebellar-ataxia-type-3/