Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3.
Ataxia
Drosophila
Isoform
Neurodegeneration
Polyglutamine
Proteasome
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
04
06
2019
revised:
05
07
2019
accepted:
12
07
2019
pubmed:
17
7
2019
medline:
28
7
2020
entrez:
17
7
2019
Statut:
ppublish
Résumé
The most commonly inherited dominant ataxia, Spinocerebellar Ataxia Type 3 (SCA3), is caused by a CAG repeat expansion that encodes an abnormally long polyglutamine (polyQ) repeat in the disease protein ataxin-3, a deubiquitinase. Two major full-length isoforms of ataxin-3 exist, both of which contain the same N-terminal portion and polyQ repeat, but differ in their C-termini; one (denoted here as isoform 1) contains a motif that binds ataxin-3's substrate, ubiquitin, whereas the other (denoted here as isoform 2) has a hydrophobic tail. Most SCA3 studies have focused on isoform 1, the predominant version in mammalian brain, yet both isoforms are present in brain and a better understanding of their relative pathogenicity in vivo is needed. We took advantage of the fruit fly, Drosophila melanogaster to model SCA3 and to examine the toxicity of each ataxin-3 isoform. Our assays reveal isoform 1 to be markedly more toxic than isoform 2 in all fly tissues. Reduced toxicity from isoform 2 is due to much lower protein levels as a result of its expedited degradation. Additional studies indicate that isoform 1 is more aggregation-prone than isoform 2 and that the C-terminus of isoform 2 is critical for its enhanced proteasomal degradation. According to our results, although both full-length, pathogenic ataxin-3 isoforms are toxic, isoform 1 is likely the primary contributor to SCA3 due to its presence at higher levels. Isoform 2, as a result of rapid degradation that is dictated by its tail, is unlikely to be a key player in this disease. Our findings provide new insight into the biology of this ataxia and the cellular processing of the underlying disease protein.
Identifiants
pubmed: 31310802
pii: S0969-9961(19)30203-7
doi: 10.1016/j.nbd.2019.104535
pmc: PMC6834911
mid: NIHMS1538510
pii:
doi:
Substances chimiques
Drosophila Proteins
0
Protein Isoforms
0
Repressor Proteins
0
ATXN3 protein, human
EC 3.4.19.12
Ataxin-3
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104535Subventions
Organisme : NINDS NIH HHS
ID : R01 NS038712
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS086778
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS104326
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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