Using Drosophila models of Huntington's disease as a translatable tool

Lewis, Elizabeth; Smith, Gaynor A.

doi:10.1016/j.jneumeth.2015.07.026

Cited by 28 publications

(20 citation statements)

References 114 publications

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“…HD has been modelled several times in Drosophila by overexpression of pathological expansions under neuronal drivers ( Lewis and Smith, 2016 ), and these models have similar phenotypes to ours, having reduced lifespan when expressed under elav-Gal4 and retinal neuron degeneration under GMR-Gal4 ( Fig. 4 ); and in addition, they also show features typical of HD, such as protein aggregates.…”

Section: Resultssupporting

confidence: 69%

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

Calpena

Amo

Chakraborty

et al. 2018

Disease Models &Amp; Mechanisms

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Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, a jp Drosophila model could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner in Drosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in a Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts.

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Section: Resultssupporting

confidence: 69%

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

Calpena

Amo

Chakraborty

et al. 2018

Disease Models &Amp; Mechanisms

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show abstract

“…Currently, genetic animal models are the most valuable tools that provide trustworthy information in order to understand the systemic and molecular dynamics, develop novel therapeutic strategies, and improve the quality of life of the affected patients and their offspring. Genetic HD animal models include transgenic, knock-in, and gene mutations in nonhuman primates, sheep, pig, mouse, zebrafish, and the fruit fly [4,5,6,7,8,9,10]; as well as diverse cell line models such as HdhQ7/111 and STHdhQ111 [11,12,13]. …”

Section: Introductionmentioning

confidence: 99%

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

Rosas‐Arellano

Estrada-Mondragón

Piña

et al. 2018

IJMS

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The average life expectancy for humans has increased over the last years. However, the quality of the later stages of life is low and is considered a public health issue of global importance. Late adulthood and the transition into the later stage of life occasionally leads to neurodegenerative diseases that selectively affect different types of neurons and brain regions, producing motor dysfunctions, cognitive impairment, and psychiatric disorders that are progressive, irreversible, without remission periods, and incurable. Huntington’s disease (HD) is a common neurodegenerative disorder. In the 25 years since the mutation of the huntingtin (HTT) gene was identified as the molecule responsible for this neural disorder, a variety of animal models, including the fruit fly, have been used to study the disease. Here, we review recent research that used Drosophila as an experimental tool for improving knowledge about the molecular and cellular mechanisms underpinning HD.

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“…Sci. 2021, 22, 3884 2 of 16 organism and its short lifespan [10]. Drosophila models reproduce many features of the human pathology, including CAG repeat length dependence of neurodegeneration, and have also been used to investigate HD in peripheral tissues [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway

Martin

Heidari

Monnier

et al. 2021

IJMS

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Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.

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Using Drosophila models of Huntington's disease as a translatable tool

Cited by 28 publications

References 114 publications

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

The Tiny Drosophila Melanogaster for the Biggest Answers in Huntington’s Disease

Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway

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