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PMID:18337722

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Citation

Lim, J, Crespo-Barreto, J, Jafar-Nejad, P, Bowman, AB, Richman, R, Hill, DE, Orr, HT and Zoghbi, HY (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452:713-8

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

Links

PubMed PMC2377396 Online version:10.1038/nature06731

Keywords

Alleles; Animals; Ataxin-1; Ataxins; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster; Humans; Mice; Multiprotein Complexes/chemistry; Multiprotein Complexes/metabolism; Nerve Tissue Proteins/chemistry; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Nuclear Proteins/chemistry; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Open Reading Frames/genetics; Peptides/genetics; Peptides/metabolism; Protein Binding; Protein Structure, Quaternary; Purkinje Cells/cytology; Purkinje Cells/metabolism; RNA Splicing Factors; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Repressor Proteins/metabolism; Ribonucleoprotein, U2 Small Nuclear/genetics; Ribonucleoprotein, U2 Small Nuclear/metabolism; Spinocerebellar Ataxias/genetics; Spinocerebellar Ataxias/metabolism; Spinocerebellar Ataxias/pathology; Trinucleotide Repeat Expansion/genetics; Two-Hybrid System Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ATX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96I25

F

Seeded From UniProt

complete

HUMAN:ATX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96RK0

F

Seeded From UniProt

complete

MOUSE:ATX1

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ATX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8JZX4

F

Seeded From UniProt

complete

MOUSE:ATX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q924A2

F

Seeded From UniProt

complete

MOUSE:ATX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q924A2

F

Seeded From UniProt

complete

DROME:Q7PL81

involved_in

GO:0001745: compound eye morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

HGNC:10548

P

Seeded From UniProt

complete

DROME:Q7PL82

involved_in

GO:0001745: compound eye morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

HGNC:10548

P

Seeded From UniProt

complete

DROME:Q7PL83

involved_in

GO:0001745: compound eye morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

HGNC:10548

P

Seeded From UniProt

complete

MOUSE:SPF45

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SPF45

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SPF45

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P54254

F

Seeded From UniProt

complete

DROME:Q8SYI1

involved_in

GO:0001745: compound eye morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

HGNC:10548

P

Seeded From UniProt

complete

MOUSE:CIC

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CIC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P54254

F

Seeded From UniProt

complete

MOUSE:CIC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54254

F

Seeded From UniProt

complete

HUMAN:SPF45

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54253

F

Seeded From UniProt

complete

HUMAN:CIC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54253

F

Seeded From UniProt

complete

HUMAN:ATX1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54253

F

Seeded From UniProt

complete

Notes

See also

References

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