AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington’s disease

2012 ◽  
Vol 420 (3) ◽  
pp. 558-563 ◽  
Author(s):  
Amparo Zuleta ◽  
Rene L. Vidal ◽  
Donna Armentano ◽  
Geoffrey Parsons ◽  
Claudio Hetz
Keyword(s):  
Transcription Factor ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin

scholarly journals Caspase-6 does not contribute to the proteolysis of mutant huntingtin in the HdhQ150 knock-in mouse model of Huntington’s disease

PLoS Currents ◽  
2012 ◽  
Vol 4 ◽  
pp. e4fd085bfc9973 ◽  
Author(s):  
Christian Landles ◽  
Andreas Weiss ◽  
Sophie Franklin ◽  
David Howland ◽  
Gill Bates
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Caspase 6

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 Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease

2014 ◽  
Vol 20 (5) ◽  
pp. 536-541 ◽  
Author(s):  
Nan Wang ◽  
Michelle Gray ◽  
Xiao-Hong Lu ◽  
Jeffrey P Cantle ◽  
Sandra M Holley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin

scholarly journals A YAC Mouse Model for Huntington’s Disease with Full-Length Mutant Huntingtin, Cytoplasmic Toxicity, and Selective Striatal Neurodegeneration

Neuron ◽  
1999 ◽  
Vol 23 (1) ◽  
pp. 181-192 ◽  
Author(s):  
J.Graeme Hodgson ◽  
Nadia Agopyan ◽  
Claire-Anne Gutekunst ◽  
Blair R Leavitt ◽  
Fred LePiane ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Full Length ◽  
Mutant Huntingtin

scholarly journals Global Rhes knockout in the Q175 Huntington’s disease mouse model

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258486
Author(s):  
Taneli Heikkinen ◽  
Timo Bragge ◽  
Juha Kuosmanen ◽  
Teija Parkkari ◽  
Sanna Gustafsson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
The Body ◽  
Mutant Huntingtin ◽  
Polyglutamine Tract ◽  
Severe Pathology ◽  
Expansion Mutation ◽  
Q175 Mice ◽  
Mixed Gender

Huntington’s disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has been reported to modulate mTOR and sumoylation of mutant huntingtin to alter HD mouse model pathogenesis. Reports have varied on whether Rhes reduction is desirable for HD. Here we characterize multiple behavioral and molecular endpoints in the Q175 HD mouse model with genetic Rhes knockout (KO). Genetic RhesKO in the Q175 female mouse resulted in both subtle attenuation of Q175 phenotypic features, and detrimental effects on other kinematic features. The Q175 females exhibited measurable pathogenic deficits, as measured by MRI, MRS and DARPP32, however, RhesKO had no effect on these readouts. Additionally, RhesKO in Q175 mixed gender mice deficits did not affect mTOR signaling, autophagy or mutant huntingtin levels. We conclude that global RhesKO does not substantially ameliorate or exacerbate HD mouse phenotypes in Q175 mice.

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