title: Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: McCullough
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Xu
authors.forename: Sharon Y R
authors.initials: SY
authors.lastname: Dent
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Grant
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000067719:Ataxin-7; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D016086:Lentivirus / Q000187:drug effects / Q000235:genetics; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D000091042:Reelin Protein; C097188:polyglutamine; C012589:trichostatin A; C000717127:RELN protein, human; D012697:Serine Endopeptidases