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Neurobiol Dis. 2019 Aug 2:104564. doi: 10.1016/j.nbd.2019.104564. [Epub ahead of print]

5'UTR-mediated regulation of Ataxin-1 expression.

Author information

1
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA.
2
Pacific Biosciences, Inc., Menlo Park, CA 94025, USA.
3
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA. Electronic address: edrod@ufl.edu.

Abstract

Expression of mutant Ataxin-1 with an abnormally expanded polyglutamine domain is necessary for the onset and progression of spinocerebellar ataxia type 1 (SCA1). Understanding how Ataxin-1 expression is regulated in the human brain could inspire novel molecular therapies for this fatal, dominantly inherited neurodegenerative disease. Previous studies have shown that the ATXN1 3'UTR plays a key role in regulating the Ataxin-1 cellular pool via diverse post-transcriptional mechanisms. Here we show that elements within the ATXN1 5'UTR also participate in the regulation of Ataxin-1 expression. PCR and PacBio sequencing analysis of cDNA obtained from control and SCA1 human brain samples revealed the presence of three major, alternatively spliced ATXN1 5'UTR variants. In cell-based assays, fusion of these variants upstream of an EGFP reporter construct revealed significant and differential impacts on total EGFP protein output, uncovering a type of genetic rheostat-like function of the ATXN1 5'UTR. We identified ribosomal scanning of upstream AUG codons and increased transcript instability as potential mechanisms of regulation. Importantly, transcript-based analyses revealed significant differences in the expression pattern of ATXN1 5'UTR variants between control and SCA1 cerebellum. Together, the data presented here shed light into a previously unknown role for the ATXN1 5'UTR in the regulation of Ataxin-1 and provide new opportunities for the development of SCA1 therapeutics.

KEYWORDS:

5′untranslated region; Alternative splicing; Ataxin-1; Cerebellum; Post-transcriptional gene regulation; Spinocerebellar ataxia type 1; Upstream AUG

PMID:
31381977
DOI:
10.1016/j.nbd.2019.104564
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