Premium
Protein surveillance machinery in brains with spinocerebellar ataxia type 3: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions
Author(s) -
Schmidt Thorsten,
Lindenberg Katrin S.,
Krebs Antje,
Schöls Ludger,
Laccone Franco,
Herms Jochen,
Rechsteiner Martin,
Riess Olaf,
Landwehrmeyer G. Bernhard
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10101
Subject(s) - spinocerebellar ataxia , proteasome , biology , microbiology and biotechnology , neurodegeneration , protein subunit , ataxia , ubiquitin , proteolysis , nucleus , neuroscience , pathology , genetics , biochemistry , medicine , gene , disease , enzyme
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 Hsp90α 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.