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

Publication date: Jan 13, 2020

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.

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Vernizzi, L., Paiardi, C., Licata, G., Vitali, T., Santarelli, S., Raneli, M., , Manelli, Rizzetto, M., Gioria, M., Pasini, M.E., Grifoni, D., Vanoni, M.A., Gellera, C., Taroni, F., and Bellosta, P. Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease. 06886. 2020 Cells (9):1.

Concepts Keywords
Amino Acids Neuron
Arginine Glutamic acid
Asparagine Neurodegeneration
ATP MTOR
Autophagy Huntingtin
Catalyzes Glutamine synthetase
Drosophila Autophagy
Enzyme Branches of biology
Essential Amino Acids Glutamate
Glia Starvation
Glutamate Neurodegenerative diseases
Glutamine
GS1
Homeostasis
Huntingtin
Huntington
Motility
Mutant
Neurodegenerative Diseases
Neurons
Phenotype
Phosphorylation
S6K

Semantics

Type Source Name
drug DRUGBANK L-Glutamine
pathway KEGG Autophagy
drug DRUGBANK ATP
drug DRUGBANK Glutamic Acid
disease MESH neurodegenerative diseases
disease MESH defects
drug DRUGBANK Amino acids
drug DRUGBANK L-Arginine
drug DRUGBANK L-Asparagine
disease MESH starvation
drug DRUGBANK Coenzyme M
disease MESH cognitive decline
disease MESH pathology
drug DRUGBANK Ammonia
drug DRUGBANK Proline
disease MESH aging
drug DRUGBANK Propanoic acid
drug DRUGBANK Ethionamide
drug DRUGBANK Phosphate ion
drug DRUGBANK Spinosad
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Edetic Acid
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Human Serum Albumin
drug DRUGBANK Tromethamine
drug DRUGBANK Microcrystalline cellulose
drug DRUGBANK Acetate ion
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK Galactose
drug DRUGBANK L-Lysine
disease MESH separated
drug DRUGBANK Nitrogen
drug DRUGBANK Methionine
drug DRUGBANK Methionine sulfoximine
disease MESH Death
drug DRUGBANK Albendazole
drug DRUGBANK Aspartame
disease MESH multiple
disease MESH development
pathway KEGG Phagosome
drug DRUGBANK L-Threonine

Original Article

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