Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, inherited disease that leads to degeneration of Purkinje cells of the cerebellum and culminates in death 10-30 years after disease onset. Patients first present with mild problems with coordination and balance (ataxia). SCA1 is caused by a CAG repeat mutation in the ATXN1 gene, encoding the ATXN1 protein with an abnormally expanded polyglutamine (polyQ) tract. As neurodegeneration progresses, other brain regions get involved and contribute to cognitive deficits as well as problems with speech, swallowing, and control of breathing. The fundamental basis of pathology is an aberration in the normal function of Purkinje cells affecting regulation of RNA splicing and gene transcription. Glutamine-expanded ATXN1 is highly stable and more resistant to degradation. Moreover, phosphorylation at S776 in ATXN1 is a post-translational modification known to influence protein levels. Studies are proposed here to examine the cellular mechanisms by which ATXN1 clearance is regulated in cerebellar Purkinje cells (PCs), a primary site of pathology in SCA1. Praja2 is an E3 ubiquitin-protein ligase that mediates polyubiquitination of target proteins. Preliminary observations show that Praja2 knockdown in PCs in vivo results in abnormally elevated levels of ATXN1 protein. Praja2 is highly expressed in PCs and, intriguingly, is significantly downregulated in cerebella of SCA1 mouse models, suggesting this pathway may be affected in disease. This revised proposal will explore Praja2 regulation of ATXN1 clearance in PCs and how that may be dependent on polyQ expansion and/or S776 phosphorylation status.
The first aim will examine whether knocking down Praja2 modulates ATXN1 levels in cerebellar PCs in vivo.
The second aim i n this proposal is to examine whether Praja2 is a ubiquitin-protein ligase to ATXN1.
The third aim will examine whether modulating Praja2 levels in PCs in vivo impacts SCA1 pathology in animal models. A better understanding of how ATXN1 clearance is regulated in vivo may provide feasible avenues for the long-term goal of developing a therapy to treat SCA1.

Public Health Relevance

Spinocerebellar ataxia type 1 (SCA1) is a fatal, inherited neurodegenerative disorder that afflicts 1-2 in 100,000 people. There is no cure for SCA1 and patient care is primarily focused on quality of life, which inevitably and steadily deteriorates. Understanding the cellular pathways that drive pathogenesis is a key goal of our lab in the light that findings will better guide strategies for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Neurological Sciences Training Initial Review Group (NST)
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Gwinn, Katrina
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University of Minnesota Twin Cities
Schools of Medicine
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Pérez Ortiz, Judit M; Mollema, Nissa; Toker, Nicholas et al. (2018) Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiol Dis 116:93-105