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.

scholarly journals Mutant Huntingtin Affects Diabetes and Alzheimer’s Markers in Human and Cell Models of Huntington’s Disease

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 962 ◽  
Author(s):  
Gepoliano Chaves ◽  
John Stanley ◽  
Nader Pourmand
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Genome Wide Association Study ◽  
Cell Model ◽  
Statistical Significance ◽  
Mutant Huntingtin ◽  
Rna Seq ◽  
Genome Wide ◽  
A Genome ◽  
Reliable Model

A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.

scholarly journals The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model

BMC Genomics ◽  
2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Martijn van Hagen ◽  
Diewertje G. E. Piebes ◽  
Wim C. de Leeuw ◽  
Ilona M. Vuist ◽  
Willeke M. C. van Roon-Mom ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
Aggregate Formation ◽  
Early State ◽  
Transcriptional Changes ◽  
Disease Cell

scholarly journals N-Terminal Proteolysis of Full-Length Mutant Huntingtin in an Inducible PC12 Cell Model of Huntington’s Disease

Cell Cycle ◽  
2007 ◽  
Vol 6 (23) ◽  
pp. 2970-2981 ◽  
Author(s):  
Tamara Ratovitski ◽  
Masayuki Nakamura ◽  
James D'Ambola ◽  
Ekaterine Chighladze ◽  
Yideng Liang ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pc12 Cell ◽  
Cell Model ◽  
Full Length ◽  
Mutant Huntingtin

Compounds blocking mutant huntingtin toxicity identified using a Huntington's disease neuronal cell model

2005 ◽  
Vol 20 (2) ◽  
pp. 500-508 ◽  
Author(s):  
Wenfei Wang ◽  
Wenzhen Duan ◽  
Shuichi Igarashi ◽  
Hokuto Morita ◽  
Masayuki Nakamura ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
Neuronal Cell ◽  
Mutant Huntingtin

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.

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