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Author Notes:

E-mail: xli2@emory.edu.

Author contributions: B.E.W., S.L., and X.-J.L. designed research; B.E.W., C.-E.W., S.Y., K.B., and B.H. performed research; B.E.W. and X.-J.L. analyzed data; B.E.W., S.L., and X.-J.L. wrote the paper.

We thank Matthew Randolph for technical assistance in muscle injection and stereotaxic surgery, Dr. Michael Epstein for recommendations in statistical analysis, Cheryl Strauss for critically reading this manuscript, and Dr. Nick Seyfried for the SUMO-2/3 antibody.

The authors declare no competing financial interests.


Research Funding:

This work was supported by National Institutes of Health Grants AG19206 and NS041449 (to X.-J.L.); and AG031153 and NS0405016 (to S.L.).

This research project was supported in part by the Viral Vector Core of the Emory National Institute of Neurological Disorders and Stroke Core Facilities Grant P30NS055077.


  • misfolding
  • neurodegneration
  • ubiquitin

Ubiquitin-Activating Enzyme Activity Contributes to Differential Accumulation of Mutant Huntingtin in Brain and Peripheral Tissues


Journal Title:

Journal of Neuroscience Nursing


Volume 34, Number 25


, Pages 8411-8422

Type of Work:

Article | Final Publisher PDF


Huntington's disease (HD) belongs to a family of neurodegenerative diseases caused by misfolded proteins and shares the pathological hallmark of selective accumulation of misfolded proteins in neuronal cells. Polyglutamine expansion in the HD protein, huntingtin (Htt), causes selective neurodegeneration that is more severe in the striatum and cortex than in other brain regions, but the mechanism behind this selectivity is unknown. Here we report that in HD knock-in mice, the expression levels of mutant Htt (mHtt) are higher in brain tissues than in peripheral tissues. However, the expression of N-terminal mHtt via stereotaxic injection of viral vectors in mice also results in greater accumulation of mHtt in the striatum than in muscle. We developed an in vitro assay that revealed that extracts from the striatum and cortex promote the formation of high-molecular weight (HMW) mHtt compared with the relatively unaffected cerebellar and peripheral tissue extracts. Inhibition of ubiquitin-activating enzyme E1 (Ube1) increased the levels of HMW mHtt in the relatively unaffected tissues. Importantly, the expression levels of Ube1 are lower in brain tissues than peripheral tissues and decline in the nuclear fraction with age, which is correlated with the increased accumulation of mHtt in the brain and neuronal nuclei during aging. Our findings suggest that decreased targeting of misfolded Htt to the proteasome for degradation via Ube1 may underlie the preferential accumulation of toxic forms of mHtt in the brain and its selective neurodegeneration.

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© 2014 the authors

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