Deciphering the Roles of Trehalose and Hsp104 in the Inhibition of Aggregation of Mutant Huntingtin in a Yeast Model of Huntington’s Disease

Chaudhary, Rajeev; Kardani, Jay; Singh, Kuljit; Banerjee, Ruchira; Roy, Ipsita

doi:10.1007/s12017-013-8275-5

Cited by 28 publications

(18 citation statements)

References 64 publications

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“…No difference in expression of Hsf1, Hsp26 or Hsp104 was seen in yeast cells expressing 25Q-htt and 103Q-htt (Fig. S3), confirming that the heat shock response is not induced in cells expressing the aggregated protein [22,52]. When the protein expression levels of Hsf1 and Hsp104 were compared across parental and ΔGpd1 cells, significant overexpression of the chaperones was seen in the deletion mutant (Fig.…”

Section: Gpd1 Is a Negative Regulator Of Heat Shock Response In Yeastsupporting

confidence: 53%

Gpd1 Regulates the Activity of Tcp-1 and Heat Shock Response in Yeast Cells: Effect on Aggregation of Mutant Huntingtin

Bhadra

Roy

2015

Mol Neurobiol

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A significant correlation has been observed between the length of the polyglutamine tract in huntingtin, its aggregation and the progression of Huntington's disease (HD). The chaperonin TRiC is a potent antagonist of aggregation of mutant huntingtin. Using the well-validated Saccharomyces cerevisiae model of HD, we have investigated the role of age-related post-translational modifications of this heterooligomeric chaperonin on its ability to inhibit aggregation of the mutant protein. We show that the glycerol synthetic enzyme Gpd1 is involved in the post-translational modification of Tcp-1 (subunit of TRiC) by acetylation and glycation through the NAD(+)/NADH shuttle and the triose phosphate intermediate dihydroxyacetone phosphate, respectively. The extent of modification of Tcp-1 shows a negative correlation with the solubility of mutant huntingtin. The absence of Gpd1 also induces heat shock response in yeast cells, further inhibiting aggregation of the mutant protein. Thus, Gpd1 acts as a major regulator of the protein folding machinery in the yeast model of HD. Modification and inactivation of cellular chaperonin are accelerated in an aging cell, which has further deleterious effects for a cell harbouring misfolded/aggregated protein(s).

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Section: Gpd1 Is a Negative Regulator Of Heat Shock Response In Yeastsupporting

confidence: 53%

Gpd1 Regulates the Activity of Tcp-1 and Heat Shock Response in Yeast Cells: Effect on Aggregation of Mutant Huntingtin

Bhadra

Roy

2015

Mol Neurobiol

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“…Trehalose is shown to protect against hypoxic and anoxic injuries and suppress protein aggregation (44, 75). In vivo findings have revealed that trehalose-induced autophagy may facilitate the clearance of mutant forms of protein aggregates in neurodegenerative disorders such as Huntington and Parkinson diseases in murine models (6, 44, 76, 77). As an autophagy inducer, trehalose may turn on autophagy in an mTOR-independent manner (42).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin resistance-associated myocardial anomalies are reminiscent of those found in diabetic individuals with compromised heart function, characterized by impaired ventricular compliance, prolonged action potential duration and ventricular diastole, and delayed cytosolic Ca 2+ clearance (3–5). It is suggested that compromised insulin signaling in the heart plays an important role in insulin resistance-induced myocardial contractile and geometric anomalies (6, 7). Within the complex insulin regulatory signaling cascade, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway governs the metabolic properties of insulin and serves as an essential gate-keeper for post-insulin receptor signaling transduction (8, 9).…”

Section: Introductionmentioning

confidence: 99%

mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1

Wang

Ren

2016

Pharmacological Research

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Insulin resistance is associated with cardiovascular diseases although the precise mechanisms remain elusive. Akt2, a critical member of the Akt family, plays an essential role in insulin signaling. This study was designed to examine the effect of trehalose, an mTOR-independent autophagy inducer, on myocardial function in an Akt2 knockout-induced insulin resistance model. Adult WT and Akt2 knockout (Akt2−/−) mice were administered trehalose (1 mg/g/day, i.p.) for two days and were then given 2% trehalose in drinking water for two more months. Echocardiographic and myocardial mechanics, intracellular Ca2+ properties, glucose tolerance, and autophagy were assessed. Apoptosis and ER stress were evaluated using TUNEL staining, Caspase 3 assay and Western blot. Autophagy and autophagy flux were examined with a focus on p38 mitogen activated protein kinase (MAPK), Forkhead box O (Foxo1) and Akt. Akt2 ablation impaired glucose tolerance, myocardial geometry and function accompanied with pronounced apoptosis, ER stress and dampened autophagy, the effects of which were ameliorated by trehalose treatment. Inhibition of lysosomal activity using bafilomycin A1 negated trehalose–induced induction of autophagy (LC3B–II and p62). Moreover, phosphorylation of p38 MAPK and Foxo1 were upregulated in Akt2−/− mice, the effect of which was attenuated by trehalose. Phosphorylation of Akt was suppressed in Akt2−/− mice and was unaffected by trehalose. In vitro findings revealed that the p38 MAPK activator anisomycin and the Foxo1 inhibitor (through phosphorylation) AS1842856 effectively masked trehalose-offered beneficial cardiomyocyte contractile response against Akt2 ablation. These data suggest that trehalose may rescue against insulin resistance-induced myocardial contractile defect and apoptosis, via autophagy associated with dephosphorylation of p38 MAPK and Foxo1 without affecting phosphorylation of Akt.

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“…Trehalose is an important storage molecule that has been suggested to be a longevity assurance sugar in C. elegans [51] , and is considered to be a stress responsive metabolite. Trehalose has been proposed to play a role against oxidative and osmotic stresses and in protein stabilization [52–54] . As previously described [33,43] , trehalose accumulates to higher levels in daf-2 mutants than in wild type animals in a DAF-16 independent manner [43] .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the effect of the mitochondrial prohibitin complex, a context-dependent modulator of longevity, on the C. elegans metabolome

Lourenço

Muñoz-Jiménez

Venegas-Calerón

et al. 2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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The mitochondrial prohibitin complex, composed of two proteins, PHB-1 and PHB-2, is a context-dependent modulator of longevity. Specifically, prohibitin deficiency shortens the lifespan of otherwise wild type worms, while it dramatically extends the lifespan under compromised metabolic conditions. This extremely intriguingly phenotype has been linked to alterations in mitochondrial function and in fat metabolism. However, the true function of the mitochondrial prohibitin complex remains elusive. Here, we used gas chromatography coupled to a flame ionization detector (GC/FID) and 1H NMR spectroscopy to gain molecular insights into the effect of prohibitin depletion on the Caenorhabditis elegans metabolome. We analysed the effect of prohibitin deficiency in two different developmental stages and under two different conditions, which result in opposing longevity phenotypes, namely wild type worms and daf-2(e1370) insulin signalling deficient mutants. Prohibitin depletion was shown to alter the fatty acid (GC/FID) and 1H NMR metabolic profiles of wild type animals both at the fourth larval stage of development (L4) and at the young adult (YA) stage, while being more pronounced at the later stage. Furthermore, wild type and the diapause mutant daf-2(e1370), either expressing or not prohibitin, were clearly distinguishable based on their metabolic profiles, revealing changes in fatty acid composition, as well as in carbohydrate and amino acid metabolism. Moreover, the metabolic data indicate that daf-2(e1370) mutants are more robust than the wild type animals to changes induced by prohibitin depletion. The impact of prohibitin depletion on the C. elegans metabolome will be discussed herein in the scope of its effect on longevity. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. Guest Editor: Aleksandra Trifunovic

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Deciphering the Roles of Trehalose and Hsp104 in the Inhibition of Aggregation of Mutant Huntingtin in a Yeast Model of Huntington’s Disease

Cited by 28 publications

References 64 publications

Gpd1 Regulates the Activity of Tcp-1 and Heat Shock Response in Yeast Cells: Effect on Aggregation of Mutant Huntingtin

Gpd1 Regulates the Activity of Tcp-1 and Heat Shock Response in Yeast Cells: Effect on Aggregation of Mutant Huntingtin

mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1

Analysis of the effect of the mitochondrial prohibitin complex, a context-dependent modulator of longevity, on the C. elegans metabolome

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