{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:03:03Z","timestamp":1791846183318,"version":"4.3.4"},"reference-count":78,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["20140703"],"award-info":[{"award-number":["20140703"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Huntington Disease Network","award":["689"],"award-info":[{"award-number":["689"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019s 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\u2019 levels that induce a \u201cstarvation-like\u201d 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.<\/jats:p>","DOI":"10.3390\/cells9010196","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T03:20:22Z","timestamp":1579058422000},"page":"196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington\u2019s Disease"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4938-9806","authenticated-orcid":false,"given":"Luisa","family":"Vernizzi","sequence":"first","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Paiardi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusimaria","family":"Licata","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Vitali","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Santarelli","sequence":"additional","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology (CiBio), University of Trento, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martino","family":"Raneli","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3222-3092","authenticated-orcid":false,"given":"Vera","family":"Manelli","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Rizzetto","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosa","family":"Gioria","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7476-6928","authenticated-orcid":false,"given":"Maria E.","family":"Pasini","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7429-4062","authenticated-orcid":false,"given":"Daniela","family":"Grifoni","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-732X","authenticated-orcid":false,"given":"Maria A.","family":"Vanoni","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Gellera","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-5233","authenticated-orcid":false,"given":"Franco","family":"Taroni","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-5661","authenticated-orcid":false,"given":"Paola","family":"Bellosta","sequence":"additional","affiliation":[{"name":"Department of Biosciences, University of Milan, 20133 Milan, Italy"},{"name":"Department of Cellular, Computational and Integrative Biology (CiBio), University of Trento, 38123 Trento, Italy"},{"name":"Department of Medicine, NYU Langone Medical Center, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,13]]},"reference":[{"key":"ref_1","unstructured":"Genetic Modifiers of Huntington\u2019s Disease Consortium (2019). 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