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Human Molecular Genetics Advance Access originally published online on January 20, 2005
Human Molecular Genetics 2005 14(5):679-691; doi:10.1093/hmg/ddi064
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved

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. Bowman1,3, Seung-Yun Yoo2,{dagger}, Nico P. Dantuma4 and Huda Y. Zoghbi1,2,3,*

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

* To whom correspondence should be addressed. Tel: +1 7137986558; Fax: +1 7137988728; Email: hzoghbi{at}bcm.tmc.edu

Received January 3, 2005; Revised January 10, 2005; Accepted January 13, 2005

The accumulation of protein deposits in neurons, in vitro proteasome assays and over-expression studies suggest that 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 among 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. Altogether, 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.

{dagger} Present address: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.


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