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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a CAG tract in the  ATXN2  gene. The SCA2 phenotype is characterized by cerebellar ataxia, neuropathy and slow saccades. SCA2 foreshortens life span and is currently without symptomatic or disease-modifying treatments. Identifying function-specific therapeutics for SCA2 is problematic due to the limited knowledge of  ATXN2  function. As SCA2 is likely caused by a gain-of-toxic or gain-of-normal function like other polyglutamine disorders, targeting  ATXN2  expression may represent a valid therapeutic approach. This study characterized aspects of  ATXN2  expression control using an  ATXN2  promoter-luciferase (luc) reporter construct. We verified the fidelity of construct expression by generating transgenic mice expressing the reporter construct. High reporter expression was seen in the cerebellum and olfactory bulb  in vivo  but there was relatively low expression in other tissues, similar to the expression of endogenous ataxin-2. We verified the second of two possible start codons as the functional start codon in  ATXN2 . By evaluating deletions in the  ATXN2  promoter, we identified an E-twenty six (ETS)-binding site required for  ATXN2  expression. We verified that endogenous ETS1 interacted with the  ATXN2  promoter by an electromobility supershift assay and chromatin immunoprecipitation polymerase chain reaction. ETS1 overexpression increased  ATXN2-luc  (ATXN2-luciferase) as well as endogenous  ATXN2  expression. Deletion of the putative ETS1-binding site abrogated the effects on the expression of  ATXN2-luc . A dominant negative ETS1 and an ETS1 short-hairpin RNA both reduced  ATXN2-luc  expression. Our study broadens the understanding on the transcriptional control of  ATXN2  and reveals specific regulatory features of the  ATXN2  promoter that can be exploited therapeutically.

ETS1 regulates the expression of ATXN2