{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:01:34Z","timestamp":1776322894123,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T00:00:00Z","timestamp":1574812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS073813"],"award-info":[{"award-number":["NS073813"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NCL Stiftung","award":["grant"],"award-info":[{"award-number":["grant"]}]},{"name":"Foundation for JNCL Research","award":["grant"],"award-info":[{"award-number":["grant"]}]},{"DOI":"10.13039\/100016948","name":"Tau Consortium","doi-asserted-by":"publisher","award":["grant"],"award-info":[{"award-number":["grant"]}],"id":[{"id":"10.13039\/100016948","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stuart &amp; Suzanne Steele MGH Research Scholars Program","award":["grant"],"award-info":[{"award-number":["grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alterations in the autophagosomal\u2013lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal\u2013lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts.<\/jats:p>","DOI":"10.3390\/cells8121531","type":"journal-article","created":{"date-parts":[[2019,11,28]],"date-time":"2019-11-28T08:14:04Z","timestamp":1574928844000},"page":"1531","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["An Autophagy Modifier Screen Identifies Small Molecules Capable of Reducing Autophagosome Accumulation in a Model of CLN3-Mediated Neurodegeneration"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-3867","authenticated-orcid":false,"given":"Anton","family":"Petcherski","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Center for Membrane Proteomics, Goethe University of Frankfurt, 60438 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7848-1102","authenticated-orcid":false,"given":"Uma","family":"Chandrachud","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5956-6434","authenticated-orcid":false,"given":"Elisabeth","family":"Butz","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine","family":"Klein","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Ning","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surya","family":"Reis","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Haggarty","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Ruonala","sequence":"additional","affiliation":[{"name":"Center for Membrane Proteomics, Goethe University of Frankfurt, 60438 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Cotman","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"International Batten Disease Consortium (1995). Isolation of a novel gene underlying Batten disease, CLN3. Cell, 82, 949\u2013957.","DOI":"10.1016\/0092-8674(95)90274-0"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10545-011-9421-6","article-title":"Females experience a more severe disease course in Batten disease","volume":"35","author":"Cialone","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1212\/WNL.0b013e31821435bd","article-title":"Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease)","volume":"76","author":"Ostergaard","year":"2011","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2217\/clp.11.70","article-title":"The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking","volume":"7","author":"Cotman","year":"2012","journal-title":"Clin. Lipidol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.bbadis.2013.01.009","article-title":"Use of model organisms for the study of neuronal ceroid lipofuscinosis","volume":"1832","author":"Bond","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1750-3639.2004.tb00501.x","article-title":"The intracellular location and function of proteins of neuronal ceroid lipofuscinoses","volume":"14","author":"Ezaki","year":"2004","journal-title":"Brain Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/jnc.13744","article-title":"Revisiting the neuronal localization and trafficking of CLN3 in juvenile neuronal ceroid lipofuscinosis","volume":"139","author":"Oetjen","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_8","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_9","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_10","doi-asserted-by":"crossref","first-page":"20483","DOI":"10.1074\/jbc.M602180200","article-title":"Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis","volume":"281","author":"Cao","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/j.1471-4159.2010.07158.x","article-title":"Lithium rescues the impaired autophagy process in CbCln3\u0394ex7\/8\/\u0394ex7\/8 cerebellar cells and reduces neuronal vulnerability to cell death via IMPase inhibition","volume":"116","author":"Chang","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Vidal-Donet, J.M., Carcel-Trullols, J., Casanova, B., Aguado, C., and Knecht, E. (2013). Alterations in ROS activity and lysosomal pH account for distinct patterns of macroautophagy in LINCL and JNCL fibroblasts. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055526"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14361","DOI":"10.1074\/jbc.M114.621706","article-title":"Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function","volume":"290","author":"Chandrachud","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_14","first-page":"7060","article-title":"Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3\u0394ex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)","volume":"24","author":"Calvi","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1093\/hmg\/11.22.2709","article-title":"Cln3\u2206ex7\/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth","volume":"11","author":"Cotman","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14338","DOI":"10.1038\/ncomms14338","article-title":"mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases","volume":"8","author":"Palmieri","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fossale, E., Wolf, P., Espinola, J.A., Lubicz-Nawrocka, T., Teed, A.M., Gao, H., Rigamonti, D., Cattaneo, E., MacDonald, M.E., and Cotman, S.L. (2004). Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMC Neurosci., 5.","DOI":"10.1186\/1471-2202-5-57"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R100","DOI":"10.1186\/gb-2006-7-10-r100","article-title":"CellProfiler: Image analysis software for identifying and quantifying cell phenotypes","volume":"7","author":"Carpenter","year":"2006","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/ncb2204","article-title":"Lysosomal positioning coordinates cellular nutrient responses","volume":"13","author":"Korolchuk","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1093\/hmg\/ddt596","article-title":"Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway","volume":"23","author":"Lojewski","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cao, Y., Staropoli, J.F., Biswas, S., Espinola, J.A., Macdonald, M.E., Lee, J.M., and Cotman, S.L. (2011). Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit C accumulation in cerebellar cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017118"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"445","DOI":"10.4161\/auto.19496","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"8","author":"Klionsky","year":"2012","journal-title":"Autophagy"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays","volume":"4","author":"Zhang","year":"1999","journal-title":"J. Biomol. Screen."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/ajmg.1320310624","article-title":"Abnormal cathepsin B activity in Batten disease","volume":"31","author":"Dawson","year":"1988","journal-title":"Am. J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7883","DOI":"10.1073\/pnas.112632299","article-title":"Neuronal loss and brain atrophy in mice lacking cathepsins B and L.","volume":"99","author":"Felbor","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13024-017-0196-6","article-title":"The lysosomal protein cathepsin L is a progranulin protease","volume":"12","author":"Lee","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_30","first-page":"747","article-title":"Loperamide blocks high-voltage-activated calcium channels and N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons","volume":"45","author":"Church","year":"1994","journal-title":"Mol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1476-5381.1990.tb15784.x","article-title":"Selective antagonism of calcium channel activators by fluspirilene","volume":"100","author":"Kenny","year":"1990","journal-title":"Br. J. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5122","DOI":"10.1073\/pnas.80.16.5122","article-title":"Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists","volume":"80","author":"Gould","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"61","DOI":"10.4161\/auto.6.1.10326","article-title":"Control of basal autophagy by calpain1 mediated cleavage of ATG5","volume":"6","author":"Xia","year":"2010","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"927","DOI":"10.4161\/auto.7.8.15862","article-title":"Regulation of autophagy by lysosomal positioning","volume":"7","author":"Korolchuk","year":"2011","journal-title":"Autophagy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1247\/csf.08005","article-title":"Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes","volume":"33","author":"Kimura","year":"2008","journal-title":"Cell Struct. Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1016\/j.biocel.2004.02.003","article-title":"Microtubule disruption inhibits autophagosome-lysosome fusion: Implications for studying the roles of aggresomes in polyglutamine diseases","volume":"36","author":"Webb","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"40282","DOI":"10.1074\/jbc.M508786200","article-title":"HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin","volume":"280","author":"Iwata","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1600-0854.2005.00368.x","article-title":"Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes","volume":"7","author":"Kochl","year":"2006","journal-title":"Traffic"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1242\/jcs.196287","article-title":"Mechanisms and functions of lysosome positioning","volume":"129","author":"Pu","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1111\/febs.14064","article-title":"Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism","volume":"284","author":"Kania","year":"2017","journal-title":"FEBS J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19023","DOI":"10.1073\/pnas.0709695104","article-title":"Small molecule regulators of autophagy identified by an image-based high-throughput screen","volume":"104","author":"Zhang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12864","DOI":"10.1073\/pnas.1509536112","article-title":"A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy","volume":"112","author":"Whitehead","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"260161","DOI":"10.1155\/2015\/260161","article-title":"Neuroprotective Effect of Simvastatin via Inducing the Autophagy on Spinal Cord Injury in the Rat Model","volume":"2015","author":"Gao","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.taap.2016.06.006","article-title":"Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects: Role of liposolubility and autophagic flux and antagonism by cholesterol ablation","volume":"305","author":"Parks","year":"2016","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4629495","DOI":"10.1155\/2017\/4629495","article-title":"Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases","volume":"2017","author":"Mancinelli","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fnagi.2018.00004","article-title":"Autophagy and Alzheimer\u2019s Disease: From Molecular Mechanisms to Therapeutic Implications","volume":"10","author":"Uddin","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.tcb.2011.11.003","article-title":"Cdk5: A multifaceted kinase in neurodegenerative diseases","volume":"22","author":"Cheung","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1023\/A:1024136318779","article-title":"Effects of cytochrome P450 inhibitors on agonist-induced Ca2+ responses and production of NO and PGI2 in vascular endothelial cells","volume":"248","author":"Takeuchi","year":"2003","journal-title":"Mol. Cell. Biochem."},{"key":"ref_49","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_50","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.1038\/ncomms5834","article-title":"Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers","volume":"5","author":"Park","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejphar.2011.03.048","article-title":"Selective dihydropyiridine compounds facilitate the clearance of beta-amyloid across the blood-brain barrier","volume":"659","author":"Bachmeier","year":"2011","journal-title":"Eur. J. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Huang, B.R., Chang, P.C., Yeh, W.L., Lee, C.H., Tsai, C.F., Lin, C., Lin, H.Y., Liu, Y.S., Wu, C.Y., and Ko, P.Y. (2014). Anti-neuroinflammatory effects of the calcium channel blocker nicardipine on microglial cells: Implications for neuroprotection. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091167"},{"key":"ref_53","first-page":"211","article-title":"Lysosomal storage of the DCCD reactive proteolipid subunit of mitochondrial ATP synthase in human and ovine ceroid lipofuscinoses","volume":"266","author":"Palmer","year":"1989","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/ajmg.1320420428","article-title":"Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease)","volume":"42","author":"Palmer","year":"1992","journal-title":"Am. J. Med. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bbagen.2010.09.004","article-title":"Screening for calcium channel modulators in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells reveals a significant decrease of intracellular calcium levels by selected L-type calcium channel blockers","volume":"1810","author":"Narayan","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/hmg\/ddl466","article-title":"Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin","volume":"16","author":"Chang","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10545-016-9986-1","article-title":"Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease","volume":"40","author":"Kwon","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.bbrc.2013.04.113","article-title":"Amlodipine prevents apoptotic cell death by correction of elevated intracellular calcium in a primary neuronal model of Batten disease (CLN3 disease)","volume":"436","author":"Warnock","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","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 diseases","volume":"285","author":"Renna","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"466","DOI":"10.15698\/mic2015.12.241","article-title":"A central role for TOR signalling in a yeast model for juvenile CLN3 disease","volume":"2","author":"Bond","year":"2015","journal-title":"Microb. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"73","DOI":"10.15252\/emmm.201505966","article-title":"The awesome lysosome","volume":"8","author":"Ballabio","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fcell.2019.00113","article-title":"The Lysosome Signaling Platform: Adapting With the Times","volume":"7","author":"Inpanathan","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41556-018-0244-7","article-title":"The lysosome as a cellular centre for signalling, metabolism and quality control","volume":"21","author":"Lawrence","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"12412","DOI":"10.1038\/s41598-017-12603-0","article-title":"Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo","volume":"7","author":"Fuller","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1093\/hmg\/ddr088","article-title":"The Batten disease gene CLN3 is required for the response to oxidative stress","volume":"20","author":"Tuxworth","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"C1388","DOI":"10.1152\/ajpcell.00272.2009","article-title":"Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla","volume":"298","author":"Stein","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18065","DOI":"10.1523\/JNEUROSCI.0498-13.2013","article-title":"CLN3 loss disturbs membrane microdomain properties and protein transport in brain endothelial cells","volume":"33","author":"Tecedor","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Getty, A., Kovacs, A.D., Lengyel-Nelson, T., Cardillo, A., Hof, C., Chan, C.H., and Pearce, D.A. (2013). Osmotic stress changes the expression and subcellular localization of the Batten disease protein CLN3. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066203"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1016\/j.bbadis.2018.08.013","article-title":"Cln3 function is linked to osmoregulation in a Dictyostelium model of Batten disease","volume":"1864","author":"Mathavarajah","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1002\/jnr.21015","article-title":"Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments","volume":"84","author":"Luiro","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/j.yexcr.2008.06.016","article-title":"Novel interactions of CLN3 protein link Batten disease to dysregulation of fodrin-Na+, K+ ATPase complex","volume":"314","author":"Luiro","year":"2008","journal-title":"Exp. Cell Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Schultz, M.L., Tecedor, L., Stein, C.S., Stamnes, M.A., and Davidson, B.L. (2014). CLN3 deficient cells display defects in the ARF1-Cdc42 pathway and actin-dependent events. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096647"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.yexcr.2010.09.007","article-title":"A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3\u2212\/\u2212 cells","volume":"317","author":"Getty","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1093\/hmg\/ddh321","article-title":"Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway","volume":"13","author":"Luiro","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"165530","DOI":"10.1016\/j.bbadis.2019.08.006","article-title":"Simvastatin induces autophagic flux to restore cerulein-impaired phagosome-lysosome fusion in acute pancreatitis","volume":"1865","author":"Piplani","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_76","unstructured":"Ruonala, M.O., Krokfors, A.I., Ramos-Moreno, J., Hooff, G.P., Hillert, R., Schubert, W., Braczynski, A., Mittelbronn, M., Wolf, P., and Cotman, S.L. Mevalonate pathway is a potential therapy target in juvenile neuronal ceroid lipofuscinosis, (In preparation)."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1531\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:38:07Z","timestamp":1760189887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1531"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,27]]},"references-count":76,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121531"],"URL":"https:\/\/doi.org\/10.3390\/cells8121531","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,27]]}}}