Polyglutamine expanded Ataxin-7 alters FUS localization and function in a SCA7 cell model

• Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7, are caused by the expansion of a CAG/polyglutamine repeat in a disease specific gene/protein. Misfolding and aggregation of the expanded protein can be observed in all polyQ disorders and sequestration of vital proteins into the aggregates formed have been suggested as a common pathological mechanism. FUS, an RNA binding protein, is frequently observed in polyglutamine aggregates. However, whether or not FUS disruption contributes to polyQ pathology is not clear.To address this question we used confocal microscopy, cell fractionation, filter traps and western blot, to study how FUS localization and function is affected by the SCA7 disease protein ataxin-7 (ATXN7). We found that aggregates formed by polyQ expanded ATXN7 were to a high degree also FUS positive and FUS re-distributed into the insoluble cell fraction together with mutant ATXN7. Moreover, a shift in abundance of FUS from the nucleus to the cytoplasm was observed and associated with altered levels of FUS regulated mRNAs in mutant ATXN7 expressing cells. However, some of the affected mRNAs are also regulated by the RNA binding protein TDP-43, which we could also show co-localized with ATXN7 aggregates using microscopy. Moreover, increased phosphorylation of serine 409/410 in TDP-43, which has been linked to TDP-43 neurotoxicity, could be observed in mutant ATXN7 expressing cells. Taken together, these findings lead us to conclude that disruption of FUS and also TDP-43 could potentially play a role in SCA7 pathology.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

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