scholarly journals Wild type huntingtin reduces the cellular toxicity of mutant huntingtin in mammalian cell models of Huntington's disease

2001 ◽  
Vol 38 (7) ◽  
pp. 450-452 ◽  
Author(s):  
L. W Ho
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cell ◽  
Mutant Huntingtin ◽  
Cell Models ◽  
Wild Type ◽  
Cellular Toxicity

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

Huntington's disease: from pathology and genetics to potential therapies

2008 ◽  
Vol 412 (2) ◽  
pp. 191-209 ◽  
Author(s):  
Sara Imarisio ◽  
Jenny Carmichael ◽  
Viktor Korolchuk ◽  
Chien-Wen Chen ◽  
Shinji Saiki ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Mutant Protein ◽  
Mutant Huntingtin ◽  
Genetic Screens ◽  
Wild Type ◽  
Biological Studies ◽  
Polyglutamine Tract

Huntington's disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion encoding an abnormally long polyglutamine tract in the huntingtin protein. Much has been learnt since the mutation was identified in 1993. We review the functions of wild-type huntingtin. Mutant huntingtin may cause toxicity via a range of different mechanisms. The primary consequence of the mutation is to confer a toxic gain of function on the mutant protein and this may be modified by certain normal activities that are impaired by the mutation. It is likely that the toxicity of mutant huntingtin is revealed after a series of cleavage events leading to the production of N-terminal huntingtin fragment(s) containing the expanded polyglutamine tract. Although aggregation of the mutant protein is a hallmark of the disease, the role of aggregation is complex and the arguments for protective roles of inclusions are discussed. Mutant huntingtin may mediate some of its toxicity in the nucleus by perturbing specific transcriptional pathways. HD may also inhibit mitochondrial function and proteasome activity. Importantly, not all of the effects of mutant huntingtin may be cell-autonomous, and it is possible that abnormalities in neighbouring neurons and glia may also have an impact on connected cells. It is likely that there is still much to learn about mutant huntingtin toxicity, and important insights have already come and may still come from chemical and genetic screens. Importantly, basic biological studies in HD have led to numerous potential therapeutic strategies.

scholarly journals Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease

2000 ◽  
Vol 97 (17) ◽  
pp. 9701-9705 ◽  
Author(s):  
J. Carmichael ◽  
J. Chatellier ◽  
A. Woolfson ◽  
C. Milstein ◽  
A. R. Fersht ◽  
...  
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cell ◽  
Aggregate Formation ◽  
Cell Models

scholarly journals Identifying Exosomes as a Messenger Unit During Heterochronic Parabiosis for Amelioration of Huntington’s Disease

2020 ◽  
Author(s):  
Mijung Lee ◽  
Wooseok Im ◽  
Manho Kim
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Blood Circulation ◽  
Underlying Mechanism ◽  
Mutant Huntingtin ◽  
Cellular Model ◽  
Wild Type ◽  
Mitochondria Dysfunction

Abstract Background:Huntington’s disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. We demonstrated the blood sharing effect by heterochronic parabiosis in HD and explored the underlying mechanism for transferring positive factors in the young blood serum.A shared blood circulation by heterochronic parabiosis has improved behavioral performance and HD pathology through mediation of mitochondria dysfunction and cell death. Furthermore, the messenger unit for the effective components in young blood is identified for the first time to the best of our knowledge.Methods:R6/2 mice were surgically connected with young wild-type mice (n=13), old wild-type mice (n=8), or R6/2 mice (n=6) to examine the effect of heterochronic parabiosis.Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. The in vitro cellular model of HD cells were treated by the 200 μg/mlblood serum of the young or old mice, and by the exosomes isolated from thereof. Thein vitro cellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain.Results:After the heterochronic parabiosis, the weight loss and survival of HD mice was improved, and also, mutant Huntingtin aggregation (EM48 p<0.005), improvement of mitochondria dysfunction (PGC-1a p<0.05, p-CREB/CREB p<0.005), cell death (p53 p<0.05, Bax p<0.05, Cleaved-caspase3 p<0.05),and cognition (DCX p<0.5) showed a near complete restoration. In addition, treatment of exosomes from young blood serum to thein vitro cellular model of HD improved mutant Huntingtin aggregation (EM48 p<0.05), mitochondria biogenesis (p-CREB/CREB p<0.005), cell death (p53 p<0.05, Bax p<0.005, Cleaved-caspase3 p<0.05, Bcl-2 p<0.05), and cell proliferation (WST-1 p<0.005).Conclusions:We found that the overall pathology of HD is improved by the shared blood circulation through heterochronic parabiosis, furthermore, we demonstrated that the exosomes are messengers for transferring positive factors,showing the potential of exosomes from young bloodfor the amelioration of HD.

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