Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a <i>Drosophila</i> Model for Huntington’s Disease
Luisa Vernizzi,
Chiara Paiardi,
Giusimaria Licata,
Teresa Vitali,
Stefania Santarelli,
Martino Raneli,
Vera Manelli,
Manuela Rizzetto,
Mariarosa Gioria,
Maria E. Pasini,
Daniela Grifoni,
Maria A. Vanoni,
Cinzia Gellera,
Franco Taroni,
Paola Bellosta
Affiliations
Luisa Vernizzi
Department of Biosciences, University of Milan, 20133 Milan, Italy
Chiara Paiardi
Department of Biosciences, University of Milan, 20133 Milan, Italy
Giusimaria Licata
Department of Biosciences, University of Milan, 20133 Milan, Italy
Teresa Vitali
Department of Biosciences, University of Milan, 20133 Milan, Italy
Stefania Santarelli
Department of Cellular, Computational and Integrative Biology (CiBio), University of Trento, 38123 Trento, Italy
Martino Raneli
Department of Biosciences, University of Milan, 20133 Milan, Italy
Vera Manelli
Department of Biosciences, University of Milan, 20133 Milan, Italy
Manuela Rizzetto
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
Mariarosa Gioria
Department of Biosciences, University of Milan, 20133 Milan, Italy
Maria E. Pasini
Department of Biosciences, University of Milan, 20133 Milan, Italy
Daniela Grifoni
Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
Maria A. Vanoni
Department of Biosciences, University of Milan, 20133 Milan, Italy
Cinzia Gellera
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
Franco Taroni
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
Paola Bellosta
Department of Biosciences, University of Milan, 20133 Milan, Italy
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.