scholarly journals Mutant huntingtin affects p53 function in a context‐dependent manner in a cell model of Huntington's disease

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Genevieve A. Ellison ◽  
Loren S. Garcia ◽  
Jonathan C. Cornett
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
Dependent Manner ◽  
Mutant Huntingtin ◽  
A Cell ◽  
Context Dependent

scholarly journals Calcium Handling by Endoplasmic Reticulum and Mitochondria in a Cell Model of Huntington’s Disease

PLoS Currents ◽  
2016 ◽  
Author(s):  
Agnese De Mario ◽  
Chiara Scarlatti ◽  
Veronica Costiniti ◽  
Simona Primerano ◽  
Raffaele Lopreiato ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
Calcium Handling ◽  
A Cell

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 Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington’s disease patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
C. Y. Daniel Lee ◽  
Nan Wang ◽  
Koning Shen ◽  
Matthew Stricos ◽  
Peter Langfelder ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Onset ◽  
High Sensitivity ◽  
Mutant Huntingtin ◽  
Disease Manifestation ◽  
Specific Domain ◽  
Disease States ◽  
Exon 1 ◽  
A Cell

AbstractIn Huntington’s disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.

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 Mutant Huntingtin Causes Context-Dependent Neurodegeneration in Mice with Huntington's Disease

2003 ◽  
Vol 23 (6) ◽  
pp. 2193-2202 ◽  
Author(s):  
Zhao-Xue Yu ◽  
Shi-Hua Li ◽  
Joy Evans ◽  
Ajay Pillarisetti ◽  
He Li ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Context Dependent

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

scholarly journals Regulation of miR-146a by RelA/NFkB and p53 in STHdhQ111/HdhQ111 Cells, a Cell Model of Huntington's Disease

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e23837 ◽  
Author(s):  
Jayeeta Ghose ◽  
Mithun Sinha ◽  
Eashita Das ◽  
Nihar R. Jana ◽  
Nitai P. Bhattacharyya
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Model ◽  
A Cell

scholarly journals Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ismael Al-Ramahi ◽  
Sai Srinivas Panapakkam Giridharan ◽  
Yu-Chi Chen ◽  
Samarjit Patnaik ◽  
Nathaniel Safren ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Selective Inhibition ◽  
Mutant Huntingtin ◽  
Causative Gene ◽  
Human Patient ◽  
Lipid Kinase ◽  
Huntingtin Protein ◽  
Mutant Huntingtin Protein ◽  
A Cell

The discovery of the causative gene for Huntington’s disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kγ. Pharmacological inhibition or knock-down of PIP4Kγ modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington’s disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kγ is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington’s disease, and potentially for other neurodegenerative disorders.

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