PMID- 10624951
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20190822
IS  - 0896-6273 (Print)
IS  - 0896-6273 (Linking)
VI  - 24
IP  - 4
DP  - 1999 Dec
TI  - Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while 
      accelerating polyglutamine-induced pathology in SCA1 mice.
PG  - 879-92
AB  - Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar
      ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusions (NI)
      that alter proteasome distribution in affected SCA1 patient neurons. Here, we
      observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway. While
      ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated equally well in
      vitro, the mutant form is three times more resistant to degradation. Inhibiting
      proteasomal degradation promotes ataxin-1 aggregation in transfected cells. And
      in mice, Purkinje cells that express mutant ataxin-1 but not a ubiquitin-protein 
      ligase have significantly fewer NIs. Nonetheless, the Purkinje cell pathology is 
      markedly worse than that of SCA1 mice. Taken together, NIs are not necessary to
      induce neurodegeneration, but impaired proteasomal degradation of mutant ataxin-1
      may contribute to SCA1 pathogenesis.
FAU - Cummings, C J
AU  - Cummings CJ
AD  - Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas
      77030, USA.
FAU - Reinstein, E
AU  - Reinstein E
FAU - Sun, Y
AU  - Sun Y
FAU - Antalffy, B
AU  - Antalffy B
FAU - Jiang, Y
AU  - Jiang Y
FAU - Ciechanover, A
AU  - Ciechanover A
FAU - Orr, H T
AU  - Orr HT
FAU - Beaudet, A L
AU  - Beaudet AL
FAU - Zoghbi, H Y
AU  - Zoghbi HY
LA  - eng
GR  - HD37283/HD/NICHD NIH HHS/United States
GR  - NS22920/NS/NINDS NIH HHS/United States
GR  - NS27699/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuron
JT  - Neuron
JID - 8809320
RN  - 0 (ATXN1 protein, human)
RN  - 0 (Ataxin-1)
RN  - 0 (Ataxins)
RN  - 0 (Atxn1 protein, mouse)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptides)
RN  - 0 (Ubiquitins)
RN  - 26700-71-0 (polyglutamine)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 6.- (Ligases)
SB  - IM
MH  - Animals
MH  - Ataxin-1
MH  - Ataxins
MH  - Cell Nucleus/*genetics/pathology
MH  - Cells, Cultured
MH  - Cysteine Endopeptidases/metabolism
MH  - Fluorescent Antibody Technique
MH  - HeLa Cells
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Inclusion Bodies/*genetics/pathology
MH  - Ligases/deficiency/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Confocal
MH  - Multienzyme Complexes/metabolism
MH  - Mutation/physiology
MH  - Nerve Tissue Proteins/biosynthesis/*genetics
MH  - Nuclear Proteins/biosynthesis/*genetics
MH  - Peptides/*toxicity
MH  - Phenotype
MH  - Plasmids/genetics
MH  - Proteasome Endopeptidase Complex
MH  - Purkinje Cells/metabolism/pathology/ultrastructure
MH  - Spinocerebellar Degenerations/*genetics/pathology
MH  - Ubiquitin-Protein Ligases
MH  - Ubiquitins/genetics/metabolism
EDAT- 2000/01/07 00:00
MHDA- 2000/01/07 00:01
CRDT- 2000/01/07 00:00
PHST- 2000/01/07 00:00 [pubmed]
PHST- 2000/01/07 00:01 [medline]
PHST- 2000/01/07 00:00 [entrez]
AID - S0896-6273(00)81035-1 [pii]
AID - 10.1016/s0896-6273(00)81035-1 [doi]
PST - ppublish
SO  - Neuron. 1999 Dec;24(4):879-92. doi: 10.1016/s0896-6273(00)81035-1.