Abstract
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
Highlights
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein
ATXN2 is a component of SGs16,17, we investigated if ATXN2 and STAU1 co-localized under conditions of stress
stress granules (SGs) are critical for normal RNA metabolism as they regulate translation during cellular stress
Summary
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. Reduction of Stau[1] in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2. STAU1 is a multifunctional protein involved in regulating RNA metabolism, and with mRNA transport in neuronal dendrites, and other cells in vertebrates[26,27,28,29,30]. The role of autophagy dysfunction in SCA2 pathology and its link to dysregulated mRNA levels is poorly understood
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