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Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Dec 26; Vol. 109 (52), pp. 21319-24. Date of Electronic Publication: 2012 Dec 10. - Publication Year :
- 2012
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Abstract
- Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.
- Subjects :
- Astrocytes drug effects
Ataxin-7
Cell Adhesion Molecules, Neuronal genetics
Extracellular Matrix Proteins genetics
HEK293 Cells
Histone Deacetylase Inhibitors pharmacology
Histones metabolism
Humans
Hydroxamic Acids pharmacology
Intranuclear Inclusion Bodies drug effects
Intranuclear Inclusion Bodies metabolism
Lentivirus drug effects
Lentivirus genetics
Models, Biological
Promoter Regions, Genetic genetics
Protein Binding drug effects
RNA, Messenger genetics
RNA, Messenger metabolism
Recombination, Genetic genetics
Reelin Protein
Serine Endopeptidases genetics
Transcription, Genetic drug effects
Ubiquitination drug effects
Astrocytes metabolism
Cell Adhesion Molecules, Neuronal metabolism
Extracellular Matrix Proteins metabolism
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Peptides genetics
Serine Endopeptidases metabolism
Spinocerebellar Ataxias genetics
Trinucleotide Repeat Expansion genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 52
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23236151
- Full Text :
- https://doi.org/10.1073/pnas.1218331110