{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:33:18Z","timestamp":1789720398140,"version":"4.0.1"},"reference-count":76,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin\u2013proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.<\/jats:p>","DOI":"10.3390\/ijms22147271","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T11:36:44Z","timestamp":1625571404000},"page":"7271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration"],"prefix":"10.3390","volume":"22","author":[{"given":"Merry","family":"Gunawan","sequence":"first","affiliation":[{"name":"Santen-SERI Open Innovation Centre, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choonbing","family":"Low","sequence":"additional","affiliation":[{"name":"Santen-SERI Open Innovation Centre, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Neo","sequence":"additional","affiliation":[{"name":"Santen-SERI Open Innovation Centre, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siawey","family":"Yeo","sequence":"additional","affiliation":[{"name":"Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice","family":"Ho","sequence":"additional","affiliation":[{"name":"Singapore Eye Research Institute, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veluchamy A.","family":"Barathi","sequence":"additional","affiliation":[{"name":"Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, 20 College Road, The Academia, Singapore 169856, Singapore"},{"name":"Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore"},{"name":"Academic Clinical Program in Ophthalmology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita Sookyee","family":"Chan","sequence":"additional","affiliation":[{"name":"Singapore Eye Research Institute, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najam A.","family":"Sharif","sequence":"additional","affiliation":[{"name":"Global Alliance and External Research, Santen Inc., Emeryville, CA 94608, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Santen-SERI Open Innovation Centre, 20 College Road, The Academia, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1126\/science.1067122","article-title":"Toxic Proteins in Neurodegenerative Disease","volume":"296","author":"Taylor","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fnmol.2014.00070","article-title":"The ubiquitin-proteasome system in neurodegenerative diseases: Precipitating factor, yet part of the solution","volume":"7","author":"Dantuma","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fncel.2018.00126","article-title":"Interplay between the autophagy-lysosomal pathway and the ubiquitin-proteasome system: A target for therapeutic development in Alzheimer\u2019s disease","volume":"12","author":"Bustamante","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.mam.2016.05.001","article-title":"Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways","volume":"50","author":"Raynes","year":"2016","journal-title":"Mol. Asp. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"38","DOI":"10.2174\/138920291501140306113344","article-title":"The Mechanistic Links Between Proteasome Activity, Aging and Age-related Diseases","volume":"15","author":"Saez","year":"2014","journal-title":"Curr. Genom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1097\/00001756-200208070-00018","article-title":"Proteasome inhibition causes nigral degeneration with inclusion bodies in rats","volume":"13","author":"McNaught","year":"2002","journal-title":"NeuroReport"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0304-3940(02)00296-3","article-title":"Selective loss of 20S proteasome \u03b1-subunits in the substantia nigra pars compacta in Parkinson\u2019s disease","volume":"326","author":"McNaught","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1471-4159.2010.06914.x","article-title":"Proteasome inhibition modeling nigral neuron degeneration in Parkinson\u2019s disease","volume":"115","author":"Xie","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8189","DOI":"10.1523\/JNEUROSCI.2218-08.2008","article-title":"Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies","volume":"28","author":"Bedford","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1471-4159.2004.02456.x","article-title":"A single amino acid substitution in a proteasome subunit triggers aggregation of ubiquitinated proteins in stressed neuronal cells","volume":"90","author":"Li","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.devcel.2015.02.002","article-title":"Neuronal Aggregates: Formation, Clearance, and Spreading","volume":"32","author":"Lim","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/sj.cdd.4402120","article-title":"Constitutive autophagy: Vital role in clearance of unfavorable proteins in neurons","volume":"14","author":"Komatsu","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature04724","article-title":"Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice","volume":"441","author":"Hara","year":"2006","journal-title":"Nature"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/NEN.0b013e31820376cc","article-title":"Protein Aggregation in the Aging Retina","volume":"70","author":"Leger","year":"2011","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.exer.2006.12.002","article-title":"Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina","volume":"84","author":"Kapphahn","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1006\/exer.2002.2022","article-title":"Proteasome function and protein oxidation in the aged retina","volume":"75","author":"Louie","year":"2002","journal-title":"Exp. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1111\/acel.12072","article-title":"Balance between autophagic pathways preserves retinal homeostasis","volume":"12","author":"Koga","year":"2013","journal-title":"Aging Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9986","DOI":"10.1073\/pnas.1305521110","article-title":"Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration","volume":"110","author":"Lobanova","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1167\/iovs.13-13272","article-title":"Decreased Proteasomal Activity Causes Photoreceptor Degeneration in Mice","volume":"55","author":"Ando","year":"2014","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1038\/s41467-018-04117-8","article-title":"Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration","volume":"9","author":"Lobanova","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1167\/iovs.10-7090","article-title":"Autophagy Activation in the Injured Photoreceptor Inhibits Fas-Mediated Apoptosis","volume":"52","author":"Besirli","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"433","DOI":"10.4161\/auto.4294","article-title":"Apoptosis and Autophagy in Photoreceptors Exposed to Oxidative Stress","volume":"3","author":"Kunchithapautham","year":"2007","journal-title":"Autophagy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/cdd.2014.203","article-title":"Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa","volume":"22","author":"Latorre","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mitter, S.K., Rao, H.V., Qi, X., Cai, J., Sugrue, A., Dunn, W.A., Grant, M.B., and Boulton, M.E. (2011). Autophagy in the Retina: A Potential Role in Age-Related Macular Degeneration. Adv. Exp. Med. Biol., 83\u201390.","DOI":"10.1007\/978-1-4614-0631-0_12"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.4161\/auto.36184","article-title":"Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD","volume":"10","author":"Mitter","year":"2014","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2537","DOI":"10.1038\/cddis.2016.453","article-title":"Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration","volume":"8","author":"Golestaneh","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Albarral, J.A. (2021). The Role of Autophagy in Eye Diseases. Life, 11.","DOI":"10.3390\/life11030189"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kageyama, M., Ota, T., Sasaoka, M., Katsuta, O., and Shinomiya, K. (2019). Chemical proteasome inhibition as a novel animal model of inner retinal degeneration in rats. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0217945"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1093\/embo-reports\/kve061","article-title":"Beclin\u2013phosphatidylinositol 3-kinase complex functions at the trans-Golgi network","volume":"2","author":"Kihara","year":"2001","journal-title":"EMBO Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1172\/JCI20039","article-title":"Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene","volume":"112","author":"Qu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15077","DOI":"10.1073\/pnas.2436255100","article-title":"Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor","volume":"100","author":"Yue","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","first-page":"2190","article-title":"The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid \u03b2 accumulation in mice","volume":"118","author":"Pickford","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.cmet.2012.02.011","article-title":"Autophagy Links Inflammasomes to Atherosclerotic Progression","volume":"15","author":"Razani","year":"2012","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7506","DOI":"10.1074\/jbc.M112.439935","article-title":"Autophagy Protects the Retina from Light-induced Degeneration","volume":"288","author":"Chen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1523\/JNEUROSCI.3714-07.2008","article-title":"Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model","volume":"28","author":"Soto","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ydbio.2009.12.032","article-title":"Regulation of photoreceptor gene expression by the retinal homeobox (Rx) gene product","volume":"339","author":"Pan","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.arcmed.2005.05.014","article-title":"Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death","volume":"37","author":"Camacho","year":"2006","journal-title":"Arch. Med Res."},{"key":"ref_39","first-page":"106","article-title":"Delayed increase of Ca2+ influx elicited by glutamate: Role in neuronal death","volume":"36","author":"Manev","year":"1989","journal-title":"Mol. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11064-006-9215-7","article-title":"Cytochemical Alterations in the Rat Retina by LPS Administration","volume":"32","author":"Jang","year":"2006","journal-title":"Neurochem. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-017-0149-0","article-title":"The SH-SY5Y cell line in Parkinson\u2019s disease research: A systematic review","volume":"12","author":"Xicoy","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1172\/JCI73939","article-title":"mTOR: A pharmacologic target for autophagy regulation","volume":"125","author":"Kim","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_43","first-page":"201","article-title":"Identification of a candidate therapeutic autophagy-inducing peptide","volume":"494","author":"Sumpter","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1096\/fj.10-167361","article-title":"Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-\u03b2 peptide degradation","volume":"25","author":"Vingtdeux","year":"2011","journal-title":"FASEB J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/cdd.2008.110","article-title":"Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies","volume":"16","author":"Sarkar","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_46","first-page":"2360","article-title":"Age related RGC vulnerability in an autophagy deficient mouse model","volume":"61","author":"Bell","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","first-page":"162","article-title":"Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice","volume":"19","author":"Germain","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-018-1044-5","article-title":"Rapamycin and fasting sustain autophagy response activated by ischemia\/reperfusion injury and promote retinal ganglion cell survival","volume":"9","author":"Russo","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1126\/science.1161566","article-title":"Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN\/mTOR Pathway","volume":"322","author":"Park","year":"2008","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S1074-5521(01)00056-4","article-title":"Proteasome inhibitors: From research tools to drug candidates","volume":"8","author":"Kisselev","year":"2001","journal-title":"Chem. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1080\/15548627.2018.1463121","article-title":"Inhibiting autophagy reduces retinal degeneration caused by protein misfolding","volume":"14","author":"Yao","year":"2018","journal-title":"Autophagy"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-019-1780-1","article-title":"Shifting the balance of autophagy and proteasome activation reduces proteotoxic cell death: A novel therapeutic approach for restoring photoreceptor homeostasis","volume":"10","author":"Qiu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Su, W., Li, Z., Jia, Y., and Zhuo, Y. (2014). Rapamycin Is Neuroprotective in a Rat Chronic Hypertensive Glaucoma Model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099719"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nn.4340","article-title":"Neural activity promotes long-distance, target-specific regeneration of adult retinal axons","volume":"19","author":"Lim","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37805","DOI":"10.1038\/srep37805","article-title":"mTOR regulates neuroprotective effect of immunized CD4+Foxp3+ T cells in optic nerve ischemia","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Piras, A., Gianetto, D., Conte, D., Bosone, A., and Vercelli, A. (2011). Activation of Autophagy in a Rat Model of Retinal Ischemia following High Intraocular Pressure. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022514"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kovalevich, J., and Langford, D. (2013). Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology, Springer Science and Business Media LLC.","DOI":"10.1007\/978-1-62703-640-5_2"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Bell, M., and Zempel, H. (2021). SH-SY5Y-derived neurons: A human neuronal model system for investigating TAU sorting and neuronal subtype-specific TAU vulnerability. Rev. Neurosci.","DOI":"10.20944\/preprints202006.0203.v2"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/jnr.10777","article-title":"An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells","volume":"74","author":"Maruyama","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.mcn.2011.04.002","article-title":"Insulin-like growth factor-I mediates neuroprotection in proteasome inhibition-induced cytotoxicity in SH-SY5Y cells","volume":"47","author":"Cheng","year":"2011","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"100790","DOI":"10.1016\/j.isci.2019.100790","article-title":"Dynamic Interaction of USP14 with the Chaperone HSC70 Mediates Crosstalk between the Proteasome, ER Signaling, and Autophagy","volume":"23","author":"Srinivasan","year":"2020","journal-title":"iScience"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1111\/jnc.15174","article-title":"Distinct alpha-Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH-SY5Y cells","volume":"156","author":"Pantazopoulou","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.molcel.2010.09.026","article-title":"Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress","volume":"40","author":"Sengupta","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1128\/MCB.06159-11","article-title":"Role of AMPK-mTOR-Ulk1\/2 in the regulation of autophagy: Cross talk, shortcuts, and feedbacks","volume":"32","author":"Alers","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1074\/jbc.R109.072181","article-title":"Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative dis-eases","volume":"285","author":"Renna","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nchembio.79","article-title":"Novel targets for Huntington\u2019s disease in an mTOR-independent autophagy pathway","volume":"4","author":"Williams","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1038\/sj.cdd.4402099","article-title":"Regulation of autophagy by the inositol trisphosphate receptor","volume":"14","author":"Criollo","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1083\/jcb.200504035","article-title":"Lithium induces autophagy by inhibiting inositol monophosphatase","volume":"170","author":"Sarkar","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1021\/cn500056q","article-title":"Lithium and Autophagy","volume":"5","author":"Motoi","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Thellung, S., Corsaro, A., Nizzari, M., Barbieri, F., and Florio, T. (2019). Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040901"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1172\/JCI73937","article-title":"Pharmacologic agents targeting autophagy","volume":"125","author":"Xia","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1089\/jop.2017.0125","article-title":"iDrugs and iDevices Discovery Research: Preclinical Assays, Techniques, and Animal Model Studies for Ocular Hypotensives and Neuroprotectants","volume":"34","author":"Sharif","year":"2018","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.4103\/1673-5374.235017","article-title":"Glaucomatous optic neuropathy treatment options: The promise of novel therapeutics, techniques and tools to help preserve vision","volume":"13","author":"Sharif","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20409","DOI":"10.1038\/s41598-019-56905-x","article-title":"Nafamostat and sepimostat identified as novel neuroprotective agents via NR2B N-methyl-D-aspartate receptor antagonism using a rat retinal excitotoxicity model","volume":"9","author":"Fuwa","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-57638-y","article-title":"Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats","volume":"10","author":"Sasaoka","year":"2020","journal-title":"Sci. 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