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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Astrocytes / drug effects
-
Astrocytes / metabolism*
-
Ataxin-7
-
Cell Adhesion Molecules, Neuronal / genetics
-
Cell Adhesion Molecules, Neuronal / metabolism*
-
Extracellular Matrix Proteins / genetics
-
Extracellular Matrix Proteins / metabolism*
-
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
-
Nerve Tissue Proteins / genetics*
-
Nerve Tissue Proteins / metabolism*
-
Peptides / genetics*
-
Promoter Regions, Genetic / genetics
-
Protein Binding / drug effects
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Recombination, Genetic / genetics
-
Reelin Protein
-
Serine Endopeptidases / genetics
-
Serine Endopeptidases / metabolism*
-
Spinocerebellar Ataxias / genetics*
-
Transcription, Genetic / drug effects
-
Trinucleotide Repeat Expansion / genetics*
-
Ubiquitination / drug effects
Substances
-
ATXN7 protein, human
-
Ataxin-7
-
Cell Adhesion Molecules, Neuronal
-
Extracellular Matrix Proteins
-
Histone Deacetylase Inhibitors
-
Histones
-
Hydroxamic Acids
-
Nerve Tissue Proteins
-
Peptides
-
RNA, Messenger
-
Reelin Protein
-
polyglutamine
-
trichostatin A
-
RELN protein, human
-
Serine Endopeptidases