Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Raper, Jessica; Bosinger, Steven E.; Johnson, Z.; Tharp, Gregory K.; Moran, Sean P.; Chan, Anthony W.S.

doi:10.1016/j.bbi.2016.07.004

Cited by 29 publications

(27 citation statements)

References 75 publications

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“…54 rHD6, rHD7 and rHD8 lines carry exons 1-10 of the hHTT gene coding N-terminal 508 amino acids with 67-72 CAG repeats under control of the human HTT promoter. 24,53,55…”

Section: Methodologies Can Be Technically Challengingmentioning

confidence: 99%

“…Monkey lines rHD1, rHD2, rHD3, rHD4 and rHD5 expressing 29 (single gene copy), 83 (two gene copies), 84 (two gene copies), 27 (two gene copies) and 88 (two gene copies) have been created . rHD6, rHD7 and rHD8 lines carry exons 1‐10 of the hHTT gene coding N‐terminal 508 amino acids with 67‐72 CAG repeats under control of the human HTT promoter …”

Section: Huntington's Diseasementioning

confidence: 99%

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Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Жунина

Yabbarov

Orekhov

et al. 2019

Int J Experimental Path

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Summary Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients’ quality of life and is a major health problem worldwide. The above‐mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease‐modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.

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“…54 rHD6, rHD7 and rHD8 lines carry exons 1-10 of the hHTT gene coding N-terminal 508 amino acids with 67-72 CAG repeats under control of the human HTT promoter. 24,53,55…”

Section: Methodologies Can Be Technically Challengingmentioning

confidence: 99%

Section: Huntington's Diseasementioning

confidence: 99%

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Жунина

Yabbarov

Orekhov

et al. 2019

Int J Experimental Path

View full text Add to dashboard Cite

show abstract

“…They expressed anxiety and irritability/aggression to an acute stressor as compared to control. Moreover, HD monkey exhibited increased proinflammatory cytokines and higher induction of immune pathway genes compared to controls . Another seven transgenic monkeys were produced for longitudinal studies to study the transcriptomic pattern (n = 4) or the whole brain white matter integrity (n = 3) .…”

Section: The Different Types Of Nhp Transgenic Modelsmentioning

confidence: 99%

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

Chansel‐Debordeaux

Bézard

2019

Anim Models and Exp Med

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Animal model is an essential tool in the life sciences research, notably in understanding the pathogenesis of the diseases and for further therapeutic intervention success. Rodents have been the most frequently used animals to model human disease since the establishment of gene manipulation technique. However, they remain inadequate to fully mimic the pathophysiology of human brain disease, partially due to huge differences between rodents and humans in terms of anatomy, brain function, and social behaviors. Nonhuman primates are more suitable in translational perspective. Thus, genetically modified animals have been generated to investigate neurologic and psychiatric disorders. The classical transgenesis technique is not efficient in that model; so, viral vector‐mediated transgene delivery and the new genome‐editing technologies have been promoted. In this review, we summarize some of the technical progress in the generation of an ad hoc animal model of brain diseases by gene delivery and real transgenic nonhuman primate.

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“…Studies in mice indicate that glial cells and galectin molecules contribute to enhanced inflammatory responses in HD (19,20). Furthermore, RNA-seq analysis of tissue obtained from human HD patients and HD monkey models reveals extensive transcriptional dysregulation associated with proinflammatory pathway activation (1,21,22).…”

Section: Introductionmentioning

confidence: 99%

cGAS, a DNA Sensor, Promotes Inflammatory Responses in Huntington Disease

Sharma

Sumitha

Shahani

et al. 2020

Preprint

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The genetic cause of Huntington disease (HD) is attributed to the N-terminal polyglutamine expansion of huntingtin (mHTT). mHTT, which is a ubiquitously expressed protein, induces noticeable damage to the striatum, which affects motor, psychiatric, and cognitive functions in HD individuals. Although inflammatory responses apparently precede striatal damage and an overall progression of HD, the molecular mechanisms at work remain unclear (1-6). In this study, we found that cyclic GMP-AMP synthase (cGAS), a DNA sensor, which regulates inflammation, autophagy, and cellular senescence (7-9), plays a critical role in the inflammatory responses of HD. Ribosome profiling analysis reveals that cGAS mRNA has a high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD cells, compared to the control, indicating an altered cGAS expression. Accordingly, cGAS protein levels and activity, as measured by phosphorylation of stimulator of interferon genes (STING) or TANK-binding kinase 1 (TBK1), are increased in HD striatal cells, mouse Q175HD striatum and human postmortem HD striatum, compared to the healthy control. Furthermore, cGASdependent inflammatory genes such as Cxcl10 and Ccl5 show enhanced ribosome occupancy at exon 3 and exon 1, respectively and are upregulated in HD cells. Depletion of cGAS via CRISPR/Cas-9 diminishes cGAS activity and decreases expression of inflammatory genes while suppressing the autophagy upregulation in HD cells. We additionally detected the presence of numerous micronuclei, a known inducer of cGAS, in the cytoplasm of HD cells. Overall, the data indicates that cGAS is highly upregulated in HD and mediates inflammatory and autophagy responses. Thus, targeting cGAS may offer therapeutic benefits in HD.

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Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Cited by 29 publications

References 75 publications

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

cGAS, a DNA Sensor, Promotes Inflammatory Responses in Huntington Disease

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