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

• Type of Material: Article
• Authors: Brandy Wade, Emory University; Chuan-En Wang, Emory University; Sen Yan, Emory University; Kavita Bhat, Emory University; Brenda Huang, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2014-06-18
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2014 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.0775-14.2014
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 34
• Issue: 25
• Start Page: 8411
• End Page: 8422
• Grant/Funding Information: 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.; This work was supported by National Institutes of Health Grants AG19206 and NS041449 (to X.-J.L.); and AG031153 and NS0405016 (to S.L.).
• Keywords: misfolding; neurodegneration; ubiquitin
• Research Categories: Biology, Genetics; Health Sciences, General

Abstract

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.