scholarly journals The Ubiquitin-Proteasome Pathway in Huntington's Disease

2008 ◽  
Vol 8 ◽  
pp. 421-433 ◽  
Author(s):  
Siddhartha Mitra ◽  
Steven Finkbeiner
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Inclusion Bodies ◽  
Mutant Huntingtin ◽  
Polyglutamine Expansion ◽  
Ubiquitin Proteasome Pathway ◽  
Intracellular Protein Degradation ◽  
Pathway Function ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The accumulation of mutant protein is a common feature of neurodegenerative disease. In Huntington's disease, a polyglutamine expansion in the huntingtin protein triggers neuronal toxicity. Accompanying neuronal death, mutant huntingtin aggregates in large macromolecular structures called inclusion bodies. The function of the machinery for intracellular protein degradation is linked to huntingtin toxicity and components of this machinery colocalize with inclusion bodies. An increasing body of evidence implicates the ubiquitin-proteasome pathway in the failure of cells to degrade mutant huntingtin. A number of potential mechanisms that link compromised ubiquitin-proteasome pathway function and neurodegeneration have been proposed and may offer opportunities for therapeutic intervention.

scholarly journals The Ubiquitin-Proteasome System in Huntington’s Disease: Are Proteasomes Impaired, Initiators of Disease, or Coming to the Rescue?

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Sabine Schipper-Krom ◽  
Katrin Juenemann ◽  
Eric A. J. Reits
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein A ◽  
Ubiquitin Proteasome System ◽  
Mutant Huntingtin ◽  
Polyglutamine Expansion ◽  
Ubiquitin Proteasome ◽  
Intracellular Aggregates ◽  
Polyglutamine Aggregation

Huntington’s disease is a progressive neurodegenerative disease, caused by a polyglutamine expansion in the huntingtin protein. A prominent hallmark of the disease is the presence of intracellular aggregates initiated by N-terminal huntingtin fragments containing the polyglutamine repeat, which recruit components of the ubiquitin-proteasome system. While it is commonly thought that proteasomes are irreversibly sequestered into these aggregates leading to impairment of the ubiquitin-proteasome system, the data on proteasomal impairment in Huntington’s disease is contradictory. In addition, it has been suggested that proteasomes are unable to actually cleave polyglutamine sequencesin vitro, thereby releasing aggregation-prone polyglutamine peptides in cells. Here, we discuss how the proteasome is involved in the various stages of polyglutamine aggregation in Huntington’s disease, and how alterations in activity may improve clearance of mutant huntingtin fragments.

scholarly journals Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington’s disease cell models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shreyaas Aravindan ◽  
Samantha Chen ◽  
Hannaan Choudhry ◽  
Celine Molfetta ◽  
Kuang Yu Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Inclusion Bodies ◽  
Cell Model ◽  
Mutant Huntingtin ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disease Protein ◽  
Disease Cell

Abstract Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington’s disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103QExon1-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. This effect of stabilizing osmolytes is innate, generic, countered by urea, and unaffected by HSP70 and HSC70 knockdown. A qualitatively similar result of osmolyte-induced mHtt IB formation is observed in a conditionally immortalized striatal neuron model of HD, and IB formation correlates with improved survival under stress. Increased expression of diffuse mHtt sequesters the CREB transcription factor to repress CREB-reporter gene activity. This repression is mitigated either by stabilizing osmolytes, which deplete diffuse mHtt or by urea, which negates protein–protein interaction. Our results show that stabilizing polyol osmolytes promote mHtt aggregation, alleviate CREB dysfunction, and promote survival under stress to support the hypothesis that lower molecular weight entities of disease protein are relevant pathogenic species in neurodegeneration.

The ubiquitin–proteasome pathway in viral infectionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Guang Gao ◽  
Honglin Luo
Keyword(s):  
Critical Role ◽  
Proteasome Inhibition ◽  
Degradation Pathway ◽  
Enteroviral Infection ◽  
Ubiquitin Proteasome Pathway ◽  
Potential Therapeutic Application ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function

The cellular biological function of the ubiquitin–proteasome pathway as a major intracellular protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated over the last decade. The critical role of the ubiquitin–proteasome pathway in viral pathogenesis has become increasingly apparent. Many viruses have been reported to evolve different strategies to utilize the ubiquitin–proteasome pathway for their own benefits. Here, we review the general background and function of the ubiquitin–proteasome pathway, summarize our current understanding of how viruses use this pathway to target cellular proteins, and finally, discuss the roles of this pathway in enteroviral infection, and the potential therapeutic application of proteasome inhibition in myocarditis.

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