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Human Molecular Genetics Advance Access published online on January 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi064
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation

Aaron B. Bowman 1, Seung-Yun Yoo 2, Nico P. Dantuma 3, and Huda Y. Zoghbi 4*

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 United States of America; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030 United States of America
2 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030 United States of America
3 Department of Cell and Molecular Biology, Karolinska Institute, Stockholm Sweden
4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 United States of America; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030 United States of America; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030 United States of America

* To whom correspondence should be addressed.
Huda Y. Zoghbi, E-mail: hzoghbi{at}bcm.tmc.edu


  Abstract

The accumulation of protein deposits in neurons, in vitro proteasome assays, and over-expression studies, suggest impairment of the ubiquitin-proteasome system (UPS) may be a common mechanism of pathogenesis in polyglutamine diseases, such as Huntington disease and spinocerebellar ataxias (SCAs). Using a knock-in mouse model that recapitulates the clinical features of human SCA7, including selective neuronal dysfunction, we assessed the UPS at cellular resolution using transgenic mice that express a green fluorescent protein (GFP)-based reporter substrate (UbG76V-GFP) of the UPS. The levels of the reporter remained low during the initial phase of disease, suggesting that neuronal dysfunction occurs in the presence of a functional UPS. Late in disease, we observed a significant increase in reporter levels specific to the most vulnerable neurons. Surprisingly, the basis for the increase in UbG76V-GFP protein can be explained by a corresponding increase in UbG76V-GFP mRNA in the vulnerable neurons. An in vitro assay also showed normal proteasome proteolytic activity in the vulnerable neurons. Thus, no evidence for general UPS impairment, or reduction of proteasome activity was seen. The differential increase of UbG76V-GFP amongst individual neurons directly correlated with the down regulation of a marker of selective pathology and neuronal dysfunction in SCA7. Furthermore, we observed a striking inverse correlation between the neuropathology revealed by this reporter and ataxin-7 nuclear inclusions in the vulnerable neurons. Together, these data show a protective role against neuronal dysfunction for polyglutamine nuclear inclusions and exclude significant impairment of the UPS as a necessary step for polyglutamine neuropathology.


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