scholarly journals Targeted Genetic Reduction of Mutant Huntingtin Lessens Cardiac Pathology in the BACHD Mouse Model of Huntington's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Saemi Park ◽  
Shu Hon Christopher Luk ◽  
Raj S. Bains ◽  
Daniel S. Whittaker ◽  
Emily Chiem ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Strategies ◽  
The Body ◽  
Activity Levels ◽  
Protein Levels ◽  
Pathological Cardiac Hypertrophy ◽  
Expression Of Genes ◽  
Wide Range

Individuals affected by Huntington's disease (HD) present with progressive degeneration that results in a wide range of symptoms, including cardiovascular (CV) dysfunction. The huntingtin gene (HTT) and its product are ubiquitously expressed, hence, the cardiomyopathy could also be driven by defects caused by its mutated form (mHTT) in the cardiomyocytes themselves. In the present study, we sought to determine the contribution of the mHTT expressed in the cardiomyocytes to CV symptoms. We utilized the BACHD mouse model, which exhibits many of the HD core symptoms, including CV dysfunction. This model allows the targeted genetic reduction of mHTT expression in the cardiomyocytes while maintaining the expression of the mHTT in the rest of the body. The BACHD line was crossed with a line of mice in which the expression of Cre recombinase is driven by the cardiac-specific alpha myosin-heavy chain (Myh6) promoter. The offspring of this cross (BMYO mice) exhibited a dramatic reduction in mHTT in the heart but not in the striatum. The BMYO mice were evaluated at 6 months old, as at this age, the BACHD line displays a strong CV phenotype. Echocardiogram measurements found improvement in the ejection fraction in the BMYO line compared to the BACHD, while hypertrophy was observed in both mutant lines. Next, we examined the expression of genes known to be upregulated during pathological cardiac hypertrophy. As measured by qPCR, the BMYO hearts exhibited significantly less expression of collagen1a as well as Gata4, and brain natriuretic peptide compared to the BACHD. Fibrosis in the hearts assessed by Masson's trichrome stain and the protein levels of fibronectin were reduced in the BMYO hearts compared to BACHD. Finally, we examined the performance of the mice on CV-sensitive motor tasks. Both the overall activity levels and grip strength were improved in the BMYO mice. Therefore, we conclude that the reduction of mHtt expression in the heart benefits CV function in the BACHD model, and suggest that cardiomyopathy should be considered in the treatment strategies for HD.

scholarly journals Formation of Polyglutamine Inclusions in a Wide Range of Non-CNS Tissues in the HdhQ150 Knock-In Mouse Model of Huntington's Disease

PLoS ONE ◽  
2009 ◽  
Vol 4 (11) ◽  
pp. e8025 ◽  
Author(s):  
Hilary Moffitt ◽  
Graham D. McPhail ◽  
Ben Woodman ◽  
Carl Hobbs ◽  
Gillian P. Bates
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Wide Range

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.

scholarly journals Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tiberiu Loredan Stan ◽  
Rana Soylu-Kucharz ◽  
Stephen Burleigh ◽  
Olena Prykhodko ◽  
Ling Cao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Intestinal Permeability ◽  
Intestinal Barrier ◽  
Systemic Circulation ◽  
Intestinal Lumen ◽  
Protein Levels ◽  
Junction Proteins

Abstract Huntington’s disease (HD) is a progressive, multifaceted neurodegenerative disease associated with weight loss and gut problems. Under healthy conditions, tight junction (TJ) proteins maintain the intestinal barrier integrity preventing bacterial translocation from the intestinal lumen to the systemic circulation. Reduction of TJs expression in Parkinson’s disease patients has been linked with increased intestinal permeability—leaky gut syndrome. The intestine contains microbiota, most dominant phyla being Bacteroidetes and Firmicutes; in pathogenic or disease conditions the balance between these bacteria might be disrupted. The present study investigated whether there is evidence for an increased intestinal permeability and dysbiosis in the R6/2 mouse model of HD. Our data demonstrate that decreased body weight and body length in R6/2 mice is accompanied by a significant decrease in colon length and increased gut permeability compared to wild type littermates, without any significant changes in the protein levels of the tight junction proteins (occludin, zonula occludens). Moreover, we found an altered gut microbiota in R6/2 mice with increased relative abundance of Bacteroidetes and decreased of Firmicutes. Our results indicate an increased intestinal permeability and dysbiosis in R6/2 mice and further studies investigating the clinical relevance of these findings are warranted.

scholarly journals Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of CaV1 Channels

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141985681 ◽  
Author(s):  
Artur S. Miranda ◽  
Pablo Leal Cardozo ◽  
Flavia R. Silva ◽  
Jessica M. de Souza ◽  
Isabella G. Olmo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Involuntary Movement ◽  
Neuronal Cell ◽  
The Body ◽  
Glutamate Toxicity ◽  
Wild Type ◽  
Vitro Assay

Huntington’s disease (HD) is a neurodegenerative autosomal dominant disorder, characterized by symptoms of involuntary movement of the body, loss of cognitive function, psychiatric disorder, leading inevitably to death. It has been previously described that higher levels of brain expression of Cav1 channels are involved in major neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Our results demonstrate that a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD mice) at the age of 3 and 12 months exhibits significantly increased Cav1.2 protein levels in the cortex, as compared with wild-type littermates. Importantly, electrophysiological analyses confirm a significant increase in L-type Ca2+ currents and total Ca2+ current density in cortical neurons from BACHD mice. By using an in vitro assay to measure neuronal cell death, we were able to observe neuronal protection against glutamate toxicity after treatment with Cav1 blockers, in wild-type and, more importantly, in BACHD neurons. According to our data, Cav1 blockers may offer an interesting strategy for the treatment of HD. Altogether, our results show that mutant huntingtin (mHtt) expression may cause a dysregulation of Cav1.2 channels and we hypothesize that this contributes to neurodegeneration during HD.

scholarly journals Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

2020 ◽  
Author(s):  
Ainara Elorza ◽  
Yamile Márquez ◽  
Jorge R. Cabrera ◽  
José Luis Sánchez-Trincado ◽  
María Santos-Galindo ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Loss ◽  
Splicing Factors ◽  
Post Mortem ◽  
Rna Seq ◽  
Protein Levels ◽  
Wide Range ◽  
Bona Fide

AbstractDeregulated alternative splicing has been implicated in a wide range of pathologies. Deep RNA-sequencing has revealed global mis-splicing signatures in multiple human diseases; however, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington’s disease (HD) pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the HD-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked effector genes, whose aberrant splicing is associated with decreased protein levels in HD patients and mice. In summary, our intersect-RNA-seq approach unveiled the pathogenic contribution of mis-splicing to HD and could be readily applied to other neurodegenerative diseases for which bona fide animal models are available.

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