November 1, 2019

Neurology/Neuroscience Research Seminar - Presented by Dr. Maria do Carmo Pereira da Costa, Research Assistant Professor, Department of Neurology - Friday, November 1st, 2019

12:00 PM to 1:00 PM

Biomedical Science Research Building (BSRB), Room 5515, 109 Zina Pitcher Place, Ann Arbor, MI 48109

Regulation of mutant Ataxin-3 abundance in Spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a dominant neurodegenerative disorder caused by a CAG repeat expansion encoding an abnormally long polyglutamine (polyQ) tract in the disease protein, ataxin-3 (ATXN3). No preventive treatment is yet available for SCA3/MJD. A rational therapeutic strategy for SCA3/MJD is to reduce mutant ATXN3 levels by targeting pathways that control its production or stability. Using unbiased high-throughput screens and a pipeline that integrates in vitro, ex vivo and in vivo models of SCA3/MJD we identified small-molecules and genes involved in novel molecular pathways that modulate levels of mutant ATXN3. Among several identified and validated compound hits the atypical antipsychotic, aripiprazole, and the selective serotonin reuptake inhibitor, citalopram, point for the involvement of serotonergic pathways and chaperone machinery in regulating misfolded ATXN3. Additional findings from a druggable genome siRNA screen defined the FBXL3/SCF protein ubiquitination axis, and TNF/NF-kB pathways as novel molecular pathways that regulate levels of ATXN3 protein. Our discoveries support, therefore, a potential repurpose of aripiprazole and citalopram for SCA3/MJD, and identify novel targets for therapeutic development for this incurable disease.

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