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Abstract
Spinocerebellar ataxia type 2 is a polyglutamine (polyQ) disease associated with an expanded polyQ domain within the protein product of the ATXN2 gene. Interestingly, polyQ repeat expansions in ATXN2 are also associated with amyotrophic lateral sclerosis (ALS) and parkinsonism depending upon the length of the polyQ repeat expansion. The sequence encoding the polyQ repeat also varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in ALS and parkinsonism is typically interrupted with the glutamine encoding CAA codon. Here, we asked if the purity of the CAG sequence encoding the polyQ repeat in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila. We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only repeat failed to confer toxicity, despite expression of the protein at similar levels. Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remained diffuse. The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation factor eIF4H, a known modifier of the toxic GGGGCC repeat in flies. These data indicate that ataxin-2 encoded by a pure CAG versus interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease.
Highlights
Expansions of microsatellite repeats are a cause of several neurodegenerative disorders
The sequence encoding the polyQ repeat varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in amyotrophic lateral sclerosis (ALS) and parkinsonism is typically interrupted with the glutamine encoding CAA codon
These data indicate that ataxin-2 encoded by a pure CAG versus interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease
Summary
Expansions of microsatellite repeats are a cause of several neurodegenerative disorders. A notable example is the polyglutamine (polyQ) diseases, which are caused by an expansion of a glutamine-encoding CAG-repeat in the respective disease genes, and includes six spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 17), Huntington’s disease and dentatorubral pallidoluysian atrophy [1,2]. Despite the CAG-repeat mutations occurring in a diverse set of proteins, the polyQ diseases share some key pathological mechanisms. An expanded polyQ results in aggregation of the disease protein, which causes toxicity via gain-of-function and loss-of-function effects [1,2]. An additional mechanism shared by many of the diseases caused by expansions of microsatellites (e.g. CAG, CTG and GGGGCC expansions) is toxicity induced by the structure of the expanded RNA [3,4,5]. It is known that the CAG-repeat from SCA2, SCA3 and Huntington’s disease can give rise to toxicity when the repeat is either isolated or flanked by short regions of coding sequence [12,16,17], less is known about the RNA-toxicity that arises from the CAG-repeat when embedded in the entire transcript
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