Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease

Novati, Arianna; Hentrich, Thomas; Wassouf, Zinah; Weber, Jonasz Jeremiasz; Yu-Taeger, Libo; Déglon, Nicole; Nguyen, Huu Phuc; Schulze‐Hentrich, Julia M.

doi:10.1038/s41598-018-24243-z

Cited by 12 publications

(9 citation statements)

References 89 publications

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“…New data are constantly emerging regarding transcriptional dysregulation in HD, both from human brain and from mouse models [30,58,[261][262][263][264][265][266][267]. Although as discussed above, specific transcription factors (TFs) are implicated, e.g., Foxp2 [82], it is unlikely that HD transcriptional pathology can be attributed to any single TF.…”

Section: Transcriptional Alterationsmentioning

confidence: 99%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

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Section: Transcriptional Alterationsmentioning

confidence: 99%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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“…It is widely believed that environmental exposures contribute to the vast majority of sporadic Alzheimer’s, Parkinson’s, Huntington’s and prion diseases alone or via interactions with genetic factors [45,46,47,48,49]. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders [46].…”

Section: Contribution Of Environmental Factors To Amyloid Diseasementioning

confidence: 99%

Yeast Models for Amyloids and Prions: Environmental Modulation and Drug Discovery

2019

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Amyloids are self-perpetuating protein aggregates causing neurodegenerative diseases in mammals. Prions are transmissible protein isoforms (usually of amyloid nature). Prion features were recently reported for various proteins involved in amyloid and neural inclusion disorders. Heritable yeast prions share molecular properties (and in the case of polyglutamines, amino acid composition) with human disease-related amyloids. Fundamental protein quality control pathways, including chaperones, the ubiquitin proteasome system and autophagy are highly conserved between yeast and human cells. Crucial cellular proteins and conditions influencing amyloids and prions were uncovered in the yeast model. The treatments available for neurodegenerative amyloid-associated diseases are few and their efficiency is limited. Yeast models of amyloid-related neurodegenerative diseases have become powerful tools for high-throughput screening for chemical compounds and FDA-approved drugs that reduce aggregation and toxicity of amyloids. Although some environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. Environmental stresses trigger amyloid formation and loss, acting either via influencing intracellular concentrations of the amyloidogenic proteins or via heterologous inducers of prions. Studies of environmental and physiological regulation of yeast prions open new possibilities for pharmacological intervention and/or prophylactic procedures aiming on common cellular systems rather than the properties of specific amyloids.

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“…HD patients might be exposed to both endogenous and exogenous glycolipid antigens capable of activating iNKT cells [21–23]. Thus, we wanted to determine whether activation of iNKT cells can impact the pathogenesis of HD in R6/2 Tg mice.…”

Section: Resultsmentioning

confidence: 99%

“…Endogenous [22] and exogenous [21] glycolipid antigens can activate iNKT cells in a CD1d-dependent manner. Moreover, enterogenous glycolipids derived from commensal bacteria circulate throughout the body and can also be recognized by iNKT cells [23]. It has been reported that microbial metabolites play a critical role in shaping the development and function of host immune responses [37].…”

Section: Discussionmentioning

confidence: 99%

iNKT Cell Activation Exacerbates the Development of Huntington’s Disease in R6/2 Transgenic Mice

Park

Lee

et al. 2019

Mediators of Inflammation

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Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFNγ and IL4 upon stimulation with the glycolipid α-galactosylceramide (α-GalCer). By employing both R6/2 Tg mice (murine HD model) and Jα18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that Jα18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with α-GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated α-GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.

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Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease

Cited by 12 publications

References 89 publications

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Yeast Models for Amyloids and Prions: Environmental Modulation and Drug Discovery

iNKT Cell Activation Exacerbates the Development of Huntington’s Disease in R6/2 Transgenic Mice

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