scholarly journals Management of altered metabolic activity in Drosophila model of Huntington’s disease by curcumin

2021 ◽  
pp. 153537022110469
Author(s):  
Kumari Aditi ◽  
Akanksha Singh ◽  
Mallikarjun N Shakarad ◽  
Namita Agrawal
Keyword(s):  
Body Weight ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Energy State ◽  
Curcuma Longa ◽  
Disease Stage ◽  
Bioactive Component ◽  
Drosophila Model ◽  
Advanced Disease Stage ◽  
Metabolic Activities

Huntington’s disease (HD) is a devastating polyglutamine disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions, and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease, and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin in Drosophila model of HD. Curcumin is the bioactive component of turmeric ( Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content, and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD.

scholarly journals Management of altered metabolic activity in Drosophila model of Huntington’s disease by curcumin

2021 ◽  
Author(s):  
Kumari Aditi ◽  
Akanksha Singh ◽  
Mallikarjun N Shakarad ◽  
Namita Agrawal
Keyword(s):  
Body Weight ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Energy State ◽  
Curcuma Longa ◽  
Disease Stage ◽  
Bioactive Component ◽  
Drosophila Model ◽  
Advanced Disease Stage ◽  
Metabolic Activities

ABSTRACTHuntington’s disease (HD) is a devastating polyglutamine (polyQ) disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin in Drosophila model of HD. Curcumin is bioactive component of turmeric (Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species (ROS) levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD. Phytochemicals like curcumin that can regulate multiple targets in complex diseases like HD, with least side-effects and maximum benefits, provide a better hope for the treatment of terminally-ill HD patients.

Methylene Blue Partially Rescues Heart Defects in a Drosophila Model of Huntington’s Disease

2015 ◽  
Vol 4 (2) ◽  
pp. 173-186 ◽  
Author(s):  
Raheleh Heidari ◽  
Véronique Monnier ◽  
Elodie Martin ◽  
Hervé Tricoire
Keyword(s):  
Methylene Blue ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Heart Defects ◽  
Drosophila Model

NMR Spectroscopy-based Metabolomics of Drosophila Model of Huntington’s Disease Suggests Altered Cell Energetics

2017 ◽  
Vol 16 (10) ◽  
pp. 3863-3872 ◽  
Author(s):  
Virender Singh ◽  
Raj Kumar Sharma ◽  
Thamarailingam Athilingam ◽  
Pradip Sinha ◽  
Neeraj Sinha ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drosophila Model ◽  
Altered Cell

scholarly journals Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

2021 ◽  
Vol 14 (10) ◽  
pp. 1044
Author(s):  
Letizia Pruccoli ◽  
Carlo Breda ◽  
Gabriella Teti ◽  
Mirella Falconi ◽  
Flaviano Giorgini ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Positive Impact ◽  
Neuroprotective Effects ◽  
Drosophila Model ◽  
Exon 1 ◽  
Transgenic Drosophila

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD.

scholarly journals The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Katharina Hecklau ◽  
Susanne Mueller ◽  
Stefan Paul Koch ◽  
Mustafa Hussain Mehkary ◽  
Busra Kilic ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Selective Inhibition ◽  
Skill Learning ◽  
Disease Stage ◽  
Therapeutic Effects ◽  
Modest Improvement ◽  
Symptomatic Disease ◽  
Histone Deacetylase 1 ◽  
Transcriptional Dysregulation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.

scholarly journals Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington’s Disease Status Based on Omics Data

2020 ◽  
Vol 21 (19) ◽  
pp. 7414
Author(s):  
Christiana C. Christodoulou ◽  
Margarita Zachariou ◽  
Marios Tomazou ◽  
Evangelos Karatzas ◽  
Christiana A. Demetriou ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transforming Growth Factor Beta ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
Clinical Symptoms ◽  
Age Of Onset ◽  
Binding Protein ◽  
Biological Data ◽  
Disease Stage

Huntington’s disease is a rare neurodegenerative disease caused by a cytosine–adenine–guanine (CAG) trinucleotide expansion in the Huntingtin (HTT) gene. Although Huntington’s disease (HD) is well studied, the pathophysiological mechanisms, genes and metabolites involved in HD remain poorly understood. Systems bioinformatics can reveal synergistic relationships among different omics levels and enables the integration of biological data. It allows for the overall understanding of biological mechanisms, pathways, genes and metabolites involved in HD. The purpose of this study was to identify the differentially expressed genes (DEGs), pathways and metabolites as well as observe how these biological terms differ between the pre-symptomatic and symptomatic HD stages. A publicly available dataset from the Gene Expression Omnibus (GEO) was analyzed to obtain the DEGs for each HD stage, and gene co-expression networks were obtained for each HD stage. Network rewiring, highlights the nodes that change most their connectivity with their neighbors and infers their possible implication in the transition between different states. The CACNA1I gene was the mostly highly rewired node among pre-symptomatic and symptomatic HD network. Furthermore, we identified AF198444 to be common between the rewired genes and DEGs of symptomatic HD. CNTN6, DEK, LTN1, MST4, ZFYVE16, CEP135, DCAKD, MAP4K3, NUPL1 and RBM15 between the DEGs of pre-symptomatic and DEGs of symptomatic HD and CACNA1I, DNAJB14, EPS8L3, HSDL2, SNRPD3, SOX12, ACLY, ATF2, BAG5, ERBB4, FOCAD, GRAMD1C, LIN7C, MIR22, MTHFR, NABP1, NRG2, OTC, PRAMEF12, SLC30A10, STAG2 and Y16709 between the rewired genes and DEGs of pre-symptomatic HD. The proteins encoded by these genes are involved in various biological pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase activity, cAMP response element-binding protein binding, protein tyrosine kinase activity, voltage-gated calcium channel activity, ubiquitin protein ligase activity, adenosine triphosphate (ATP) binding, and protein serine/threonine kinase. Additionally, prominent molecular pathways for each HD stage were then obtained, and metabolites related to each pathway for both disease stages were identified. The transforming growth factor beta (TGF-β) signaling (pre-symptomatic and symptomatic stages of the disease), calcium (Ca2+) signaling (pre-symptomatic), dopaminergic synapse pathway (symptomatic HD patients) and Hippo signaling (pre-symptomatic) pathways were identified. The in silico metabolites we identified include Ca2+, inositol 1,4,5-trisphosphate, sphingosine 1-phosphate, dopamine, homovanillate and L-tyrosine. The genes, pathways and metabolites identified for each HD stage can provide a better understanding of the mechanisms that become altered in each disease stage. Our results can guide the development of therapies that may target the altered genes and metabolites of the perturbed pathways, leading to an improvement in clinical symptoms and hopefully a delay in the age of onset.

Disease stage and plasma levels of cytokines in Huntington's disease: A 2-year follow-up study

2017 ◽  
Vol 32 (7) ◽  
pp. 1103-1104 ◽  
Author(s):  
J.A. Bouwens ◽  
E. van Duijn ◽  
C.M. Cobbaert ◽  
R.A.C. Roos ◽  
R.C. van der Mast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Plasma Levels ◽  
Disease Stage ◽  
Follow Up Study

scholarly journals Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington’s Disease

2018 ◽  
Vol 33 (5) ◽  
pp. 535-554 ◽  
Author(s):  
Daniel S. Whittaker ◽  
Dawn H. Loh ◽  
Huei-Bin Wang ◽  
Yu Tahara ◽  
Dika Kuljis ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Progression ◽  
Sleep Onset ◽  
Lifestyle Changes ◽  
Disease Stage ◽  
Preclinical Model ◽  
Delay Disease Progression ◽  
Circadian Dysfunction

Huntington’s disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.

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