title: Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions.
abstract: Intracellular aggregates commonly forming neuronal intranuclear inclusions are neuropathological hallmarks of spinocerebellar ataxia type 3 and of other disorders characterized by expanded polyglutamine-(poly-Q) tracts. To characterize cellular responses to these aggregates, we performed an immunohistochemical analysis of neuronal intranuclear inclusions in pontine neurons of patients affected by spinocerebellar ataxia type 3, using a panel of antibodies directed against chaperones and proteasome subunits. A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90alpha and HDJ-2, a member of the Hsp40 family. Most neuronal intranuclear inclusions were ubiquitin positive, suggesting degradation by ubiquitin-dependent proteasome pathways. Surprisingly, only a fraction of neuronal intranuclear inclusions were immunopositive for antibodies directed against subunits of the 20S proteolytic core, whereas most inclusions were stained by antibodies directed against subunits of the 11S and 19S regulatory particles. These results suggest that the proteosomal proteolytic machinery that actively degrades neuronal intranuclear inclusions is assembled in only a fraction of pontine neurons in end stage spinocerebellar ataxia type 3. The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains.
authors.affiliation: Department of Medical Genetics, University of Tübingen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Lindenberg
authors.forename: Antje
authors.initials: A
authors.lastname: Krebs
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Martin
authors.initials: M
authors.lastname: Rechsteiner
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: G Bernhard
authors.initials: GB
authors.lastname: Landwehrmeyer
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D017827:Machado-Joseph Disease / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011149:Pons / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014018:Tissue Distribution
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010450:Endopeptidases; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases