B35 Glutamine synthetase-1 induces autophagy and neuronal survival in a drosophila model huntington’s disease

2016 ◽  
Vol 87 (Suppl 1) ◽  
pp. A21.2-A21 ◽  
Author(s):  
Maria Enrica Pasini ◽  
Chiara Paiardi ◽  
Luisa Vernizzi ◽  
Alice Valenza ◽  
Giusimaria Licata ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Survival ◽  
Drosophila Model

scholarly journals Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 196 ◽  
Author(s):  
Luisa Vernizzi ◽  
Chiara Paiardi ◽  
Giusimaria Licata ◽  
Teresa Vitali ◽  
Stefania Santarelli ◽  
...  
Keyword(s):  
Amino Acids ◽  
Glutamine Synthetase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Essential Amino Acids ◽  
Mutant Huntingtin ◽  
Lysosomal Degradation ◽  
Drosophila Model ◽  
Key Enzyme ◽  
Novel Targets

Glutamine Synthetase 1 (GS1) is a key enzyme that catalyzes the ATP-dependent synthesis of l-glutamine from l-glutamate and is also member of the Glutamate Glutamine Cycle, a complex physiological process between glia and neurons that controls glutamate homeostasis and is often found compromised in neurodegenerative diseases including Huntington’s disease (HD). Here we report that the expression of GS1 in neurons ameliorates the motility defects induced by the expression of the mutant Htt, using a Drosophila model for HD. This phenotype is associated with the ability of GS1 to favor the autophagy that we associate with the presence of reduced Htt toxic protein aggregates in neurons expressing mutant Htt. Expression of GS1 prevents the TOR activation and phosphorylation of S6K, a mechanism that we associate with the reduced levels of essential amino acids, particularly of arginine and asparagine important for TOR activation. This study reveals a novel function for GS1 to ameliorate neuronal survival by changing amino acids’ levels that induce a “starvation-like” condition responsible to induce autophagy. The identification of novel targets that inhibit TOR in neurons is of particular interest for the beneficial role that autophagy has in preserving physiological neuronal health and in the mechanisms that eliminate the formation of toxic aggregates in proteinopathies.

scholarly journals Glutamine Synthetase-1 induces autophagy-lysosomal degradation of huntingtin aggregates and ameliorates animal motility in a Drosophila model for Huntington’s disease

2019 ◽  
Author(s):  
Luisa Vernizzi ◽  
Chiara Paiardi ◽  
Giusimaria Licata ◽  
Teresa Vitali ◽  
Stefania Santarelli ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Aggregates ◽  
Cellular Level ◽  
Physiological Process ◽  
Lysosomal Degradation ◽  
Tor Signaling ◽  
Beneficial Role ◽  
Drosophila Model

AbstractGlutamine Synthetase1 (GS1) is an enzyme that catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia as a key element of the glutamate glutamine cycle, a complex physiological process occurring between glia and neurons, necessary to control the homeostasis of glutamate. Using a Drosophila model for Huntington’s disease, we report that expression of GS1 in neurons ameliorates the motility defects of animals expressing the mutant Httex1-Q93 form of the huntingtin gene. At the cellular level, expression of GS1 increases the basal level of autophagy and significantly reduces the size of the toxic Htt-Q93 protein aggregates. In addition, we found that expression of GS1 prevents TOR localization at the lysosomal membrane and reduction in the phosphorylation of its effector S6K. This study reveals a novel function for GS1 in neurons linking its activity to the inhibition of TOR signaling and autophagy. The identification of novel pharmacological regulators of autophagy is of particular interest considering its beneficial role in controlling neuronal health and counteracting the detrimental effects of toxic aggregates of proteinopathies including Huntington’s disease.

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.

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