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 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 Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism

2008 ◽  
Vol 17 (20) ◽  
pp. 3223-3235 ◽  
Author(s):  
Hon Kit Wong ◽  
Peter O. Bauer ◽  
Masaru Kurosawa ◽  
Anand Goswami ◽  
Chika Washizu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Dependent Mechanism

scholarly journals Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice

2008 ◽  
Vol 180 (6) ◽  
pp. 1177-1189 ◽  
Author(s):  
Jianjun Wang ◽  
Chuan-En Wang ◽  
Adam Orr ◽  
Suzanne Tydlacka ◽  
Shi-Hua Li ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Ubiquitin Proteasome System ◽  
Synaptic Function ◽  
Fluorescent Reporters ◽  
Biochemical Assays ◽  
Neuronal Processes ◽  
Ubiquitin Proteasome ◽  
And Function ◽  
Other Neurological Disease

Huntington's disease (HD) is caused by the expansion of a polyglutamine tract in the N-terminal region of huntingtin (htt) and is characterized by selective neurodegeneration. In addition to forming nuclear aggregates, mutant htt accumulates in neuronal processes as well as synapses and affects synaptic function. However, the mechanism for the synaptic toxicity of mutant htt remains to be investigated. We targeted fluorescent reporters for the ubiquitin–proteasome system (UPS) to presynaptic or postsynaptic terminals of neurons. Using these reporters and biochemical assays of isolated synaptosomes, we found that mutant htt decreases synaptic UPS activity in cultured neurons and in HD mouse brains that express N-terminal or full-length mutant htt. Given that the UPS is a key regulator of synaptic plasticity and function, our findings offer insight into the selective neuronal dysfunction seen in HD and also establish a method to measure synaptic UPS activity in other neurological disease models.

scholarly journals Cysteine String Protein Controls Two Routes of Export for Misfolded Huntingtin

2022 ◽  
Vol 15 ◽  
Author(s):  
Desmond Pink ◽  
Julien Donnelier ◽  
John D. Lewis ◽  
Janice E. A. Braun
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Extracellular Vesicles ◽  
Molecular Chaperone ◽  
Mutant Huntingtin ◽  
Cysteine String Protein ◽  
N Terminus ◽  
Intracellular Aggregates ◽  
Transmission Of Disease

Extracellular vesicles (EVs) are secreted vesicles of diverse size and cargo that are implicated in the cell-to-cell transmission of disease-causing-proteins in several neurodegenerative diseases. Mutant huntingtin, the disease-causing entity in Huntington’s disease, has an expanded polyglutamine track at the N terminus that causes the protein to misfold and form toxic intracellular aggregates. In Huntington’s disease, mutant huntingtin aggregates are transferred between cells by several routes. We have previously identified a cellular pathway that is responsible for the export of mutant huntingtin via extracellular vesicles. Identifying the EV sub-populations that carry misfolded huntingtin cargo is critical to understanding disease progression. In this work we expressed a form of polyglutamine expanded huntingtin (GFP-tagged 72Qhuntingtinexon1) in cells to assess the EVs involved in cellular export. We demonstrate that the molecular chaperone, cysteine string protein (CSPα; DnaJC5), facilitates export of disease-causing-polyglutamine-expanded huntingtin cargo in 180–240 nm vesicles as well as larger 10–30 μm vesicles.

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