scholarly journals A Multi-omic Huntington’s Disease Transgenic Sheep-Model Database for Investigating Disease Pathogenesis

2021 ◽  
pp. 1-12
Author(s):  
Emily R. Mears ◽  
Renee R. Handley ◽  
Matthew J. Grant ◽  
Suzanne J. Reid ◽  
Benjamin T. Day ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Model Systems ◽  
Sheep Model ◽  
Tissue Samples ◽  
Proteomic Data ◽  
Alternate Model ◽  
Model Database ◽  
User Friendly ◽  
And Control

Background: The pathological mechanism of cellular dysfunction and death in Huntington’s disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control ‘omic’ profiles and reported in literature. Objective: Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. Methods: To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort of 5-year-old OVT73 (n = 6) and control (n = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. Results: We present the ‘multi-omic’ HD sheep database as a queriable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. Conclusion: We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort.

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

2018 ◽  
Vol 115 (30) ◽  
pp. E7081-E7090 ◽  
Author(s):  
Laura E. Bowie ◽  
Tamara Maiuri ◽  
Melanie Alpaugh ◽  
Michelle Gabriel ◽  
Nicolas Arbez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Oxidative Dna Damage ◽  
Model Systems ◽  
Protective Effects ◽  
Mutant Huntingtin ◽  
Naturally Occurring ◽  
Phosphate Donor ◽  
High Content Analysis

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

scholarly journals KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

2017 ◽  
Vol 114 (23) ◽  
pp. E4676-E4685 ◽  
Author(s):  
Luisa Quinti ◽  
Sharadha Dayalan Naidu ◽  
Ulrike Träger ◽  
Xiqun Chen ◽  
Kimberly Kegel-Gleason ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Model Systems ◽  
Human Model ◽  
Selective Activation ◽  
Primary Mouse

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

scholarly journals Temporal Control Deficits in Murine Models of Huntington’s Disease

2015 ◽  
Vol 28 ◽  
Author(s):  
Dani Brunner ◽  
Fuat Balcı ◽  
Paul C.P Curtin ◽  
Andrew Farrar ◽  
Steve Oakeshott ◽  
...  
Keyword(s):  
Information Processing ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Temporal Information ◽  
Temporal Control ◽  
Response Curves ◽  
Temporal Information Processing ◽  
Trial Analysis ◽  
And Control

Timing is a ubiquitous process that underlies a great variety of human activities and depends on highly conserved neuronal circuitry, the cortico-striatal loops. The peak interval (PI) task is an operant task that conditions subjects to initiate and terminate behavioral responses bracketing a fixed interval associated with reinforcement. Performance in this task depends on the efficacy of temporal control processes that coordinate interval encoding and decoding, instrumental response innitiation, cessation and maintenance, and motor control. Here, we used the PI procedure to characterize temporal control in zQ175 knockin (KI) and BAC HD transgenic (Tg) mice generated to model Huntington's Disease (HD), and contrast the result with previously published R6/2 Tg PI data. HD is a progressive neurodegenerative disorder that involves degeneration of the same neural circuits underlying temporal information processing and control of motor output. Our results indicate that temporal control is disrupted in R6/2 Tg and zQ175 KI mice but intact in BAC HD Tg mice. Trial-by-trial analysis of break-run patterns in response rates indicated that shifts in zQ175 KI response curves were driven by significant delays in response initiation and cessation. Similar temporal control deficits were previously reported in HD patients and R6/2 transgenic HD mice. These findings support the use of zQ175 mice in preclinical studies of HD-related cognitive deficits. They provide evidence of a strong homology between the human and rodent neural bases of temporal information processing, temporal response control, and their pathology in neurodegeneration.

scholarly journals Huntington's disease: from gene to potential therapy

2001 ◽  
Vol 3 (1) ◽  
pp. 17-23
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Western Europe ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Cell Metabolism ◽  
Normal Function ◽  
Model Systems

Huntington's disease (HD) is a progressive, late-onset neurodegenerative illness with autosomal dominant inheritance that affects one in 10 000 individuals in Western Europe. The disease is caused by a polyglutamine repeat expansion located in the N-terminal region of the huntingtin protein. The mutation is likely to act by a gain of function, but the molecular mechanisms by which it leads to neuronal dysfunction and cell death are not yet known. The normal function of huntingtin in cell metabolism is also unclear. There is no therapy for HD. Research on HD should help elucidate the pathogenetic mechanism of this illness in order to develop successful treatments to prevent or slow down symptoms. This article presents new results in HD research focusing on in vivo and in vitro model systems, potential molecular mechanisms of HD, and the development of therapeutic strategies.

scholarly journals Analysis of mutant and total huntingtin expression in Huntington’s disease murine models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Valentina Fodale ◽  
Roberta Pintauro ◽  
Manuel Daldin ◽  
Roberta Altobelli ◽  
Maria Carolina Spiezia ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Tissue Expression ◽  
Peripheral Tissue ◽  
Mutant Form ◽  
Murine Models ◽  
Therapeutic Approaches ◽  
And Control

AbstractHuntington’s disease (HD) is a monogenetic neurodegenerative disorder that is caused by the expansion of a polyglutamine region within the huntingtin (HTT) protein, but there is still an incomplete understanding of the molecular mechanisms that drive pathology. Expression of the mutant form of HTT is a key aspect of diseased tissues, and the most promising therapeutic approaches aim to lower expanded HTT levels. Consequently, the investigation of HTT expression in time and in multiple tissues, with assays that accurately quantify expanded and non-expanded HTT, are required to delineate HTT homeostasis and to best design and interpret pharmacodynamic readouts for HTT lowering therapeutics. Here we evaluate mutant polyglutamine-expanded (mHTT) and polyglutamine-independent HTT specific immunoassays for validation in human HD and control fibroblasts and use to elucidate the CSF/brain and peripheral tissue expression of HTT in preclinical HD models.

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