title: Differential effects of polyglutamine proteins on nuclear organization and artificial reporter splicing.
abstract: Nuclear inclusions formed by proteins with expanded polyglutamine tracts are found in several neurodegenerative diseases. The effect of nuclear inclusions formed by these disease proteins on the functional organization of the nucleus is only partially understood. In particular, it is not known whether polyglutamine disease proteins disrupt the function of Cajal bodies, which are subnuclear domains that play a role in the biogenesis of small nuclear ribonucleoproteins (snRNPs). snRNPs are an integral part of the pre-mRNA splicing machinery, so it is possible that mutant proteins that alter Cajal body activity indirectly affect pre-mRNA splicing. Here, we evaluate three different polyglutamine disease proteins--ataxin-1, ataxin-3, and huntingtin--for their ability to disrupt Cajal body localization and reduce the splicing of an artificial reporter in HeLa cells. Consistent with previous observations, ataxin-1 inclusions do not drastically alter the localization of Cajal bodies. In contrast, ataxin-3 inclusions associate with this structure. Inclusions formed by a fragment of the huntingtin protein do not associate with Cajal bodies or PML bodies, another subnuclear domain. Among the three disease proteins, only ataxin-3 significantly decreases the splicing of an artificial reporter. These results support the hypothesis that different mutant proteins vary in their ability to disrupt nuclear organization and function.
authors.affiliation: Department of Neurology, The University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
authors.forename: June
authors.initials: J
authors.lastname: Sun
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Xu
authors.forename: Sandeep
authors.initials: S
authors.lastname: Negi
authors.forename: S H
authors.initials: SH
authors.lastname: Subramony
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hebert
mesh_terms: D000067696:Ataxin-1; D000067699:Ataxin-3; D000067528:Ataxins; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D020541:Coiled Bodies / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D017404:In Situ Hybridization, Fluorescence; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012326:RNA Splicing / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D014162:Transfection
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011506:Proteins; D012097:Repressor Proteins; D017411:Ribonucleoproteins, Small Nuclear; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3