Protein surveillance machinery in brains with spinocerebellar ataxia type 3: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions
Article first published online: 27 FEB 2002
Copyright © 2002 Wiley-Liss, Inc.
Annals of Neurology
Volume 51, Issue 3, pages 302–310, March 2002
How to Cite
Schmidt, T., Lindenberg, K. S., Krebs, A., Schöls, L., Laccone, F., Herms, J., Rechsteiner, M., Riess, O. and Landwehrmeyer, G. B. (2002), Protein surveillance machinery in brains with spinocerebellar ataxia type 3: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol., 51: 302–310. doi: 10.1002/ana.10101
- Issue published online: 28 FEB 2002
- Article first published online: 27 FEB 2002
- Manuscript Revised: 5 NOV 2001
- Manuscript Accepted: 5 NOV 2001
- Manuscript Received: 23 MAY 2001
- Deutsche Forschungsgemeinschaft. Grant Numbers: Ri682/7-1 (to OR), SFB 505, TPC2 (to GBL)
- German Hereditary Ataxia Foundation (to OR)
- Graduierten-Kolleg für Molekulare Medizin (to KSL)
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.