Modulation of Huntington’s Disease in Drosophila

Subhan, Iqra; Siddique, Yasir Hasan

doi:10.2174/1871527320666210412155508

Cited by 6 publications

(7 citation statements)

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“…Several studies have connected CCT to the regulation of mutant Huntingtin (mHTT) protein, and there is some evidence that a loss of wild-type HTT disrupts neuron formation [ 63 , 64 ]. Drosophila melanogaster has been used to model many HD-related phenomena, such as motor deficits, circadian rhythm changes, metabolic precursors of disease, mHTT aggregate spreading in the brain, and more [ 65 , 66 , 67 , 68 , 69 ]. Using UAS-mediated constructs of mutant Huntingtin (see Supplementary Table S1 ), we expressed human mHTT in CIV neurons and quantified the gross morphology of the resultant dendritic arbors.…”

Section: Resultsmentioning

confidence: 99%

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CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease

Lottes,

Ciger,

Bhattacharjee

et al. 2024

Cells

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The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multi-dendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1) in vitro. Through targeted genetic manipulations, we confirm that an LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases the dendritic complexity in CIV neurons. Furthermore, both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus, we examine CIV dendritic development in disease conditions as well. The expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through the regulation of TORC1 in both health and disease.

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Section: Resultsmentioning

confidence: 99%

“…WT HTT is thought to be involved in cellular trafficking, and there is evidence that mHTT expression can destabilize MTs [ 69 , 70 ]. We predicted that there would be underlying cytoskeletal deficits in these neurons similar to the phenotypes we observe in CCT and TORC1 LOF neurons.…”

Section: Resultsmentioning

confidence: 99%

CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease

Lottes,

Ciger,

Bhattacharjee

et al. 2024

Cells

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“…HD is a complex disease with varied symptoms, including involuntary choreatic motions and motor coordination deficiencies, mild to severe cognitive decline, and psychotic and behavioural deficits [ 1 - 7 , 10 ] During the onset of HD, all these symptoms may not appear, but they worsen with age [ 1 - 7 ]. These phenotypes often manifest in middle age with cognitive and psychiatric abnormalities [ 1 - 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…HTT is about 350 kDa cytoplasmic protein with limited nuclear localization [ 9 ]. The nuclear localization sequence (NLS) of HTT is present at the N-terminus (between 174 to 207 amino acids), facilitating its nuclear interaction with karyopherin β2 [ 9 , 10 ]. This NLS is made up of three consensus sequences: a basic-charged sequence, a proline-tyrosine sequence, and a downstream-conserved arginine [ 9 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

Bhat

Ahamad

Dar

et al. 2023

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Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. Infact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibi-tors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanisms.

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“…Several HD animal models have been generated, including nematode, insect, fish, rodent or large mammals [ 18 , 19 , 20 , 21 , 22 , 23 ]. The pig models, rather than small mammals, share anatomical, physiological, and pathophysiological similarities with human, and allow the generation of genetically modified models for translational research [ 22 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

Ananbeh

Novak

Juhás

et al. 2022

IJMS

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(1) Background: Huntington’s disease (HD) is rare incurable hereditary neurodegenerative disorder caused by CAG repeat expansion in the gene coding for the protein huntingtin (HTT). Mutated huntingtin (mHTT) undergoes fragmentation and accumulation, affecting cellular functions and leading to neuronal cell death. Porcine models of HD are used in preclinical testing of currently emerging disease modifying therapies. Such therapies are aimed at reducing mHTT expression, postpone the disease onset, slow down the progression, and point out the need of biomarkers to monitor disease development and therapy efficacy. Recently, extracellular vesicles (EVs), particularly exosomes, gained attention as possible carriers of disease biomarkers. We aimed to characterize HTT and mHTT forms/fragments in blood plasma derived EVs in transgenic (TgHD) and knock-in (KI-HD) porcine models, as well as in HD patients’ plasma. (2) Methods: Small EVs were isolated by ultracentrifugation and HTT forms were visualized by western blotting. (3) Results: The full length 360 kDa HTT co-isolated with EVs from both the pig model and HD patient plasma. In addition, a ~70 kDa mutant HTT fragment was specific for TgHD pigs. Elevated total huntingtin levels in EVs from plasma of HD groups compared to controls were observed in both pig models and HD patients, however only in TgHD were they significant (p = 0.02). (4) Conclusions: Our study represents a valuable initial step towards the characterization of EV content in the search for HD biomarkers.

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Modulation of Huntington’s Disease in Drosophila

Cited by 6 publications

References 124 publications

CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease

CCT and Cullin1 Regulate the TORC1 Pathway to Promote Dendritic Arborization in Health and Disease

The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

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