{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:22:53Z","timestamp":1792264973226,"version":"4.4.0"},"reference-count":91,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science, Innovation and Universities","award":["PID2019-105795RB-I00"],"award-info":[{"award-number":["PID2019-105795RB-I00"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["PID2023-147959OB-I00"],"award-info":[{"award-number":["PID2023-147959OB-I00"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["BES-2014-067781"],"award-info":[{"award-number":["BES-2014-067781"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["BES-2017-079923"],"award-info":[{"award-number":["BES-2017-079923"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["PID2019-105795RB-I00"],"award-info":[{"award-number":["PID2019-105795RB-I00"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["PID2023-147959OB-I00"],"award-info":[{"award-number":["PID2023-147959OB-I00"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["BES-2014-067781"],"award-info":[{"award-number":["BES-2014-067781"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["BES-2017-079923"],"award-info":[{"award-number":["BES-2017-079923"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Huntington disease\u2019s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2\/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2\/DRD3 agonist treatment. Autophagy activation and its effects on mHTT\/polyQ clearance were studied in R6\/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2\/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6\/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT\/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients.<\/jats:p>","DOI":"10.3390\/cells14090652","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dopamine Receptor D3 Induces Transient, mTORC1-Dependent Autophagy That Becomes Persistent, AMPK-Mediated, and Neuroprotective in Experimental Models of Huntington\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Diego","family":"Luis-Ravelo","sequence":"first","affiliation":[{"name":"Institute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6682-6612","authenticated-orcid":false,"given":"Felipe","family":"Fumagallo-Reading","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8856-9098","authenticated-orcid":false,"given":"Alejandro","family":"Febles-Casquero","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38200 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-2615","authenticated-orcid":false,"given":"Jonathan","family":"Lopez-Fernandez","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38200 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4618-7267","authenticated-orcid":false,"given":"Daniel J.","family":"Marcellino","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Biology, Ume\u00e5 University, 901 87 Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2223-7434","authenticated-orcid":false,"given":"Tomas","family":"Gonzalez-Hernandez","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Technologies, University of La Laguna, 38200 Tenerife, Spain"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38200 Tenerife, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-017-0077-5","article-title":"Protein misfolding in neurodegenerative diseases: Implications and strategies","volume":"6","author":"Sweeney","year":"2017","journal-title":"Transl. Neurodegener."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cbpa.2018.05.018","article-title":"Therapeutic strategies for targeting neurodegenerative protein misfolding Chem disorders","volume":"44","author":"Scannevin","year":"2018","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lei, Y., and Klionsky, D.J. (2021). The emerging roles of autophagy in Human diseases. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111651"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature04724","article-title":"Suppression of basal autophagy in neuronal cells causes degenerative disease in mice","volume":"441","author":"Hara","year":"2006","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nature04723","article-title":"Loss of autophagy in the central nervous system causes neurodegeneration in mice","volume":"441","author":"Komatsu","year":"2006","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1016\/j.jmb.2019.12.035","article-title":"Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases","volume":"432","author":"Djajadikerta","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/ncb2082","article-title":"Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation","volume":"12","author":"Gao","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/ncb1482","article-title":"Calpain-mediated cleavage of Atg switches autophagy to apoptosis","volume":"8","author":"Yousefi","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.cellsig.2013.11.028","article-title":"The role of cell signalling in the crosstalk between autophagy and apoptosis","volume":"26","author":"Booth","year":"2014","journal-title":"Cell. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S1474-4422(13)70088-7","article-title":"Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington\u2019s disease in the TRACK-HD study: Analysis of 36-month observational data","volume":"12","author":"Tabrizi","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4161\/pri.1.1.4056","article-title":"Aggregation of expanded huntingtin in the brains of patients with Huntington disease","volume":"1","author":"Hoffner","year":"2007","journal-title":"Prion"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/nature02998","article-title":"Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death","volume":"431","author":"Arrasate","year":"2004","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1038\/ncomms3753","article-title":"Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress","volume":"4","author":"Leitman","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1007\/s13311-012-0112-2","article-title":"Huntington\u2019s disease and the striatal medium spiny neuron: Cell-autonomous and non-cell-autonomous mechanisms of disease","volume":"9","author":"Ehrlich","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ene.13413","article-title":"Huntington\u2019s disease: A clinical review","volume":"25","author":"McColgan","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.3174\/ajnr.A2018","article-title":"Onset and progression of pathologic atrophy in Huntington disease: A longitudinal MR imaging study","volume":"31","author":"Hobbs","year":"2010","journal-title":"Am. J. Neuroradiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0893-133X(95)00150-C","article-title":"Dopamine receptor mRNA expression in human striatum and neocortex","volume":"15","author":"Damask","year":"1996","journal-title":"Neuropsychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.brainres.2007.04.043","article-title":"Dopamine receptor mRNA and protein expression in the mouse corpus striatum and cerebral cortex during pre- and postnatal development","volume":"1156","author":"Araki","year":"2007","journal-title":"Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1080\/15548627.2019.1668606","article-title":"DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis","volume":"16","year":"2020","journal-title":"Autophagy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"ra103","DOI":"10.1126\/scisignal.2005633","article-title":"Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington\u2019s disease","volume":"7","author":"Pryor","year":"2014","journal-title":"Sci. Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.expneurol.2017.10.019","article-title":"Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington\u2019s disease","volume":"299","author":"Marcellino","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","article-title":"Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.brainres.2004.01.021","article-title":"Early exploratory behavior abnormalities in R6\/1 Huntington\u2019s disease transgenic mice","volume":"1005","author":"Bolivar","year":"2004","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1021\/acschemneuro.0c00332","article-title":"Classics in Chemical Neuroscience: Pramipexole","volume":"11","author":"Wilson","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1186\/s12883-022-02830-y","article-title":"Efficacy of pramipexole on quality of life in patients with Parkinson\u2019s disease: A systematic review and meta-analysis","volume":"22","author":"Li","year":"2022","journal-title":"BMC Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00213-007-0766-3","article-title":"Yawning and hypothermia in rats: Effects of dopamine D3 and D2 agonists and antagonists","volume":"193","author":"Collins","year":"2007","journal-title":"Psychopharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.nbd.2014.12.007","article-title":"Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake","volume":"74","author":"Moratalla","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and humans","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1471-2164-12-14","article-title":"Expression of G protein coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis","volume":"12","author":"Atwook","year":"2011","journal-title":"BMC Genom."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1021\/acs.jproteome.2c00707","article-title":"Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G-Protein- and \u03b2-Arrestin-Mediated Effects","volume":"22","author":"Wenk","year":"2023","journal-title":"J. Proteome Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1091\/mbc.e03-05-0293","article-title":"Interactions of GIPC with dopamine D2, D3 but not D4 receptors define a novel mode of regulation of G protein-coupled receptors","volume":"15","author":"Jeanneteau","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1136\/jmg.36.10.739","article-title":"A molecular investigation of true dominance in Huntington\u2019s disease","volume":"36","author":"Narain","year":"1999","journal-title":"J. Med. Genet."},{"key":"ref_34","unstructured":"Paxinos, G., and Franklin, B.J.K. (2004). The Mouse Brain in Stereotaxic Coordinates, Compact, Elsevier. [2nd ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.pharmthera.2016.06.007","article-title":"Current drug treatments targeting dopamine D3 receptor","volume":"165","author":"Leggio","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-59745-157-4_4","article-title":"LC3 and Autophagy","volume":"455","author":"Tanida","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"542","DOI":"10.4161\/auto.4600","article-title":"How to interpret LC3 immunoblotting","volume":"3","author":"Mizushima","year":"2007","journal-title":"Autophagy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (4th Edition)","volume":"17","author":"Klionsky","year":"2021","journal-title":"Autophagy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1042\/EBC20170035","article-title":"Regulation of selective autophagy: The p62\/SQSTM1 paradigm","volume":"61","author":"Lamark","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neulet.2011.08.043","article-title":"Protective role of the ubiquitin binding protein Tollip against the toxicity of polyglutamine-expansion proteins","volume":"503","author":"Oguro","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.cell.2014.05.048","article-title":"Autophagic clearance of polyQ proteins mediated by ubiquitin-Atg8 adaptors of the conserved CUET protein family","volume":"158","author":"Lu","year":"2014","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1471-4159.2004.02692.x","article-title":"Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions","volume":"91","author":"Nagaoka","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/bpa.12426","article-title":"Huntington\u2019s disease (HD): The neuropathology of a multisystem neurodegenerative disorder of the human brain","volume":"26","author":"Seidel","year":"2016","journal-title":"Brain Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/bs.apha.2020.09.004","article-title":"DARPP-32 40 years later","volume":"90","author":"Girault","year":"2021","journal-title":"Adv. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1093\/hmg\/ddg242","article-title":"DNA damage induced by polyglutamine-expanded proteins","volume":"12","author":"Giuliano","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/978-1-61779-998-3_40","article-title":"Histone H2AX phosphorylation: A marker for DNA damage","volume":"920","author":"Sharma","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1042\/BST20130134","article-title":"Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: Autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers","volume":"41","author":"Sarkar","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-981-15-0602-4_4","article-title":"AMPK and Autophagy","volume":"1206","author":"Li","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.neuropharm.2015.08.024","article-title":"Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine","volume":"99","author":"Sutton","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.pbb.2016.04.006","article-title":"Region-specific activation of the AMPK system by cocaine: The role of D1 and D2 receptors","volume":"146\u2013147","author":"Xu","year":"2016","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1124\/molpharm.121.000302","article-title":"G-Protein Coupled Receptor Signaling and Mammalian Target of Rapamycin Complex 1 Regulation","volume":"101","author":"Melick","year":"2022","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1146\/annurev-pharmtox-010611-134537","article-title":"AMPK and mTOR in cellular energy homeostasis and drug targets","volume":"52","author":"Inoki","year":"2012","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2020.01.015","article-title":"AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control","volume":"31","author":"Gonzalez","year":"2020","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"643","DOI":"10.4161\/auto.7.6.15123","article-title":"The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR","volume":"7","author":"Egan","year":"2011","journal-title":"Autophagy"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1158\/0008-5472.CAN-08-3014","article-title":"TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): Phospho-Ser2481 is a marker for intact mTOR signaling complex 2","volume":"69","author":"Copp","year":"2009","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5279","DOI":"10.1002\/j.1460-2075.1995.tb00212.x","article-title":"The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain","volume":"14","author":"Pearson","year":"1995","journal-title":"EMBO J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"27879","DOI":"10.1074\/jbc.271.44.27879","article-title":"Characterization of the AMP-activated protein kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase","volume":"271","author":"Hawley","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jmb.2019.07.016","article-title":"Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors","volume":"432","author":"Johansen","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/febs.15824","article-title":"A guide to the regulation of selective autophagy receptors","volume":"289","author":"Gubas","year":"2022","journal-title":"FEBS J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00109-020-01999-4","article-title":"Toll-interacting protein impacts on inflammation, autophagy, and vacuole trafficking in human disease","volume":"99","author":"Li","year":"2021","journal-title":"J. Mol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"793328","DOI":"10.3389\/fcell.2022.793328","article-title":"Selective Autophagy Receptor p62\/SQSTM1, a Pivotal Player in Stress and Aging","volume":"10","author":"Kumar","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/B978-0-12-397926-1.00018-4","article-title":"Toll-interacting protein pathway: Degradation of an ubiquitin-binding protein","volume":"534","author":"Shimizu","year":"2014","journal-title":"Methods Enzymol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng1362","article-title":"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease","volume":"36","author":"Ravikumar","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/nn.2528","article-title":"Cargo recognition failure is responsible for ineffective autophagy in Huntington\u2019s disease","volume":"13","author":"Talloczy","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"16889","DOI":"10.1073\/pnas.1420103111","article-title":"Potential function for the Huntingtin protein as a scaffold for selective autophagy","volume":"111","author":"Ochaba","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1523\/JNEUROSCI.1870-13.2014","article-title":"The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation","volume":"34","author":"Wong","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.molcel.2016.07.022","article-title":"Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors","volume":"63","author":"Kim","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1073\/pnas.0511256103","article-title":"Pharmacological promotion of inclusion formation: A therapeutic approach for Huntington\u2019s and Parkinson\u2019s diseases","volume":"103","author":"Bodner","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s12035-014-8932-1","article-title":"Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?","volume":"52","author":"Hoffner","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2017.08.009","article-title":"In Situ Architecture and Cellular Interactions of PolyQ Inclusions","volume":"171","author":"Saha","year":"2017","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6579","DOI":"10.1038\/s41467-021-26684-z","article-title":"Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties","volume":"12","author":"Riguet","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/nature09076","article-title":"Termination of autophagy and reformation of lysosomes regulated by mTOR","volume":"465","author":"Yu","year":"2010","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.15252\/embj.201590992","article-title":"mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival","volume":"34","author":"Munson","year":"2015","journal-title":"EMBO J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e919","DOI":"10.1038\/cddis.2013.447","article-title":"(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson\u2019s disease","volume":"4","author":"Kim","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"26758","DOI":"10.1038\/srep26758","article-title":"AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo","volume":"6","author":"Domise","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3233\/JPD-171296","article-title":"Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinsons Disease","volume":"8","author":"Curry","year":"2018","journal-title":"J. Parkinson Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"66","DOI":"10.2174\/1389203720666190819142746","article-title":"AMPK: Potential Therapeutic Target for Alzheimer\u2019s Disease","volume":"21","author":"Yang","year":"2020","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/j.1471-4159.2005.03029.x","article-title":"CGS21680 attenuates symptoms of Huntington\u2019s disease in a transgenic mouse model","volume":"93","author":"Chou","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1083\/jcb.201105010","article-title":"Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington\u2019s disease","volume":"194","author":"Ju","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neulet.2006.10.039","article-title":"Metformin therapy in a transgenic mouse model of Huntington\u2019s disease","volume":"411","author":"Ma","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1093\/hmg\/ddv513","article-title":"AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington\u2019s disease","volume":"25","author":"Farina","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Vi\u0161nji\u0107, D., Lali\u0107, H., Dembitz, V., and Smoljo, T. (2021). AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review. Cells, 10.","DOI":"10.3390\/cells10051095"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"111670","DOI":"10.1016\/j.mad.2022.111670","article-title":"Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder","volume":"204","author":"Millan","year":"2022","journal-title":"Mech. Ageing Dev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/sj.embor.7400917","article-title":"ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase","volume":"8","author":"Lee","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"737","DOI":"10.4161\/auto.7.7.15491","article-title":"ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding","volume":"7","author":"Dunlop","year":"2011","journal-title":"Autophagy"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"696","DOI":"10.4161\/auto.7.7.15451","article-title":"Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop","volume":"7","author":"Alers","year":"2011","journal-title":"Autophagy"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s42255-019-0157-1","article-title":"mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress","volume":"2","author":"Ling","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1152\/physrev.00038.2014","article-title":"mTOR in Brain Physiology and Pathologies","volume":"95","author":"Bockaert","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_89","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation","volume":"36","author":"Mendoza","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.ctrv.2013.03.009","article-title":"Targeting the PI3K\/AKT\/mTOR and Raf\/MEK\/ERK pathways in the treatment of breast cancer","volume":"39","author":"Saini","year":"2013","journal-title":"Cancer Treat. Rev."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:11Z","timestamp":1760030651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":91,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["cells14090652"],"URL":"https:\/\/doi.org\/10.3390\/cells14090652","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}