TY - JOUR
T1 - Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes
AU - McCullough, Shaun D.
AU - Xu, Xiaojiang
AU - Dent, Sharon Y.R.
AU - Bekiranov, Stefan
AU - Roeder, Robert G.
AU - Grant, Patrick A.
PY - 2012/12/26
Y1 - 2012/12/26
N2 - 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 fi ndings suggest that reelin could be a previously unknown factor involved in the tissue specifi city 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.
AB - 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 fi ndings suggest that reelin could be a previously unknown factor involved in the tissue specifi city 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.
KW - Chromatin
KW - Histone modification
KW - SAGA complex
UR - http://www.scopus.com/inward/record.url?scp=84871823260&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871823260&partnerID=8YFLogxK
U2 - 10.1073/pnas.1218331110
DO - 10.1073/pnas.1218331110
M3 - Article
C2 - 23236151
AN - SCOPUS:84871823260
SN - 0027-8424
VL - 109
SP - 21319
EP - 21324
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -