Journal Article

DZNE-2020-06762

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Physiological and pathophysiological characteristics of ataxin-3 isoforms.

Weishäupl, D. ; Schneider, J. ; Peixoto Pinheiro, B. ; Ruess, C. ; Dold, S. M. ; von Zweydorf, F.DZNE* ; Gloeckner, C. J.DZNE* ; Schmidt, J. ; Riess, O. ; Schmidt, T. (Corresponding author)

2019
Soc.60645 Bethesda, Md.

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Please use a persistent id in citations: doi:10.1074/jbc.RA118.005801

Abstract: Ataxin-3 is a deubiquitinating enzyme and the affected protein in the neurodegenerative disorder Machado-Joseph disease (MJD). The ATXN3 gene is alternatively spliced, resulting in protein isoforms that differ in the number of ubiquitin-interacting motifs. Additionally, nonsynonymous SNPs in ATXN3 cause amino acid changes in ataxin-3, and one of these polymorphisms introduces a premature stop codon in one isoform. Here, we examined the effects of different ataxin-3 isoforms and of the premature stop codon on ataxin-3's physiological function and on main disease mechanisms. At the physiological level, we show that alternative splicing and the premature stop codon alter ataxin-3 stability and that ataxin-3 isoforms differ in their enzymatic deubiquitination activity, subcellular distribution, and interaction with other proteins. At the pathological level, we found that the expansion of the polyglutamine repeat leads to a stabilization of ataxin-3 and that ataxin-3 isoforms differ in their aggregation properties. Interestingly, we observed a functional interaction between normal and polyglutamine-expanded ATXN3 allelic variants. We found that interactions between different ATXN3 allelic variants modify the physiological and pathophysiological properties of ataxin-3. Our findings indicate that alternative splicing and interactions between different ataxin-3 isoforms affect not only major aspects of ataxin-3 function but also MJD pathogenesis. Our results stress the importance of considering isoforms of disease-causing proteins and their interplay with the normal allelic variant as disease modifiers in MJD and autosomal-dominantly inherited diseases in general.

Keyword(s): Alternative Splicing (MeSH) ; Ataxin-3: analysis (MeSH) ; Ataxin-3: genetics (MeSH) ; Ataxin-3: metabolism (MeSH) ; Gene Knockdown Techniques (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Machado-Joseph Disease: genetics (MeSH) ; Machado-Joseph Disease: metabolism (MeSH) ; Machado-Joseph Disease: pathology (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Protein Aggregation, Pathological: genetics (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Protein Aggregation, Pathological: pathology (MeSH) ; Protein Interaction Maps (MeSH) ; Protein Isoforms: analysis (MeSH) ; Protein Isoforms: genetics (MeSH) ; Protein Isoforms: metabolism (MeSH) ; Protein Stability (MeSH) ; Ubiquitin: metabolism (MeSH) ; Protein Isoforms ; Ubiquitin ; Ataxin-3

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Contributing Institute(s):

1. Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases (AG Gloeckner)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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