{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:56:29Z","timestamp":1789775789480,"version":"4.0.1"},"reference-count":136,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T00:00:00Z","timestamp":1662940800000},"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>Mitochondrial dysfunction has been recognised a major contributory factor to the pathophysiology of a number of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs is as yet uncertain, but appears to be triggered by a number of different factors, although oxidative stress and impaired mitophagy appear to be common inhibitory mechanisms shared amongst this group of disorders, including Gaucher\u2019s disease, Niemann\u2013Pick disease, type C, and mucopolysaccharidosis. Many LSDs resulting from defects in lysosomal hydrolase activity show neurodegeneration, which remains challenging to treat. Currently available curative therapies are not sufficient to meet patients\u2019 needs. In view of the documented evidence of mitochondrial dysfunction in the neurodegeneration of LSDs, along with the reciprocal interaction between the mitochondrion and the lysosome, novel therapeutic strategies that target the impairment in both of these organelles could be considered in the clinical management of the long-term neurodegenerative complications of these diseases. The purpose of this review is to outline the putative mechanisms that may be responsible for the reported mitochondrial dysfunction in LSDs and to discuss the new potential therapeutic developments.<\/jats:p>","DOI":"10.3390\/ijms231810573","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T22:53:46Z","timestamp":1663023226000},"page":"10573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Secondary Mitochondrial Dysfunction as a Cause of Neurodegenerative Dysfunction in Lysosomal Storage Diseases and an Overview of Potential Therapies"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-6332","authenticated-orcid":false,"given":"Karolina M.","family":"Stepien","sequence":"first","affiliation":[{"name":"Adult Inherited Metabolic Disorders, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neve","family":"Cufflin","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Donald","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics, St Mary\u2019s Hospital, Manchester Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5117-0566","authenticated-orcid":false,"given":"Simon","family":"Jones","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics, St Mary\u2019s Hospital, Manchester Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Church","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics, St Mary\u2019s Hospital, Manchester Foundation Trust, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain P.","family":"Hargreaves","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,12]]},"reference":[{"key":"ref_1","unstructured":"Fuller, M., Meikle, P.J., and Hopwood, J.J. (2006). Epidemiology of Lysosomal Storage Diseases: An Overview, Oxford PharmaGenesis. Chapter 2."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1083\/jcb.201208152","article-title":"The cell biology of disease: Lysosomal storage disorders: The cellular impact of lysosomal dysfunction","volume":"199","author":"Platt","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1053\/siny.2001.0088","article-title":"Lysosomal disorders","volume":"7","author":"Wraith","year":"2002","journal-title":"Semin. Neonatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41572-018-0025-4","article-title":"Lysosomal storage diseases","volume":"4","author":"Platt","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1042\/BST20130083","article-title":"Metabolic and cellular bases of sphingolipidoses","volume":"41","author":"Sandhoff","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3565","article-title":"Signals from the lysosome: A control centre for cellular clearance and energy metabolism","volume":"14","author":"Settembre","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102553","DOI":"10.1016\/j.ceca.2022.102553","article-title":"TRPMLs and TPCs: Targets for lysosomal storage and neurodegenerative disease therapy?","volume":"103","author":"Krogsaeter","year":"2022","journal-title":"Cell Calcium"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tancini, B., Buratta, S., Delo, F., Sagini, K., Chiaradia, E., Pellegrino, R.M., Emiliani, C., and Urbanelli, L. (2020). Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle. Membranes, 10.","DOI":"10.3390\/membranes10120406"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0531-5565(00)00075-9","article-title":"When lysosomes get old","volume":"35","author":"Cuervo","year":"2000","journal-title":"Exp. Gerontol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12035-010-8141-5","article-title":"Mitochondrial dysfunction: Common final pathway in brain aging and Alzheimer\u2019s disease\u2014Therapeutic aspects","volume":"41","author":"Muller","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer\u2019s disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S401","DOI":"10.3233\/JAD-2010-100666","article-title":"A synergistic dysfunction of mitochondrial fission\/fusion dynamics and mitophagy in Alzheimer\u2019s disease","volume":"20","author":"Santos","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e12836","DOI":"10.15252\/emmm.202012836","article-title":"The rapidly evolving view of lysosomal storage diseases","volume":"13","author":"Parenti","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Stepien, K.M., Roncaroli, F., Turton, N., Hendriksz, C.J., Roberts, M., Heaton, R.A., and Hargreaves, I. (2020). Mechanisms of mitochondrial dysfunction in lysosomal storage disorders: A review. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082596"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/s41419-017-0025-4","article-title":"Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases","volume":"9","author":"Annunziata","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.neuint.2017.02.007","article-title":"Mitophagy in neurodegeneration and aging","volume":"109","author":"Fivenson","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1750-1326-4-24","article-title":"Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson\u2019s disease: How neurons are lost in the Bermuda triangle","volume":"4","author":"Malkus","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"150","DOI":"10.14336\/AD.2015.0820","article-title":"The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases","volume":"7","author":"Redmann","year":"2016","journal-title":"Aging Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s10545-017-0048-0","article-title":"Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases","volume":"40","author":"Saffari","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1136\/adc.2009.173419","article-title":"The epidemiology of progressive intellectual and neurological deterioration in childhood","volume":"95","author":"Verity","year":"2010","journal-title":"Arch. Dis. Child."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter analysis of glucocerebrosidase mutations in Parkinson\u2019s disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.molmed.2016.12.003","article-title":"Mitochondrial dysfunction and neurodegeneration in lysosomal storage disorders","volume":"23","author":"Plotegher","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1049793","DOI":"10.1080\/21675511.2015.1049793","article-title":"Crosstalk between 2 organelles: Lysosomal storage of heparin sulfate causes mitochondrial defects and neuronal death in mucopolysaccharidosis III type c","volume":"3","author":"Pshezhetsky","year":"2015","journal-title":"Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/brain\/awu355","article-title":"Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model","volume":"138","author":"Martins","year":"2015","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev-neuro-070815-014031","article-title":"Brain disorders due to lysosomal dysfunction","volume":"39","author":"Fraldi","year":"2016","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/jnc.14471","article-title":"Mitochondria, lysosomes, and dysfunction: Their meaning in neurodegeneration","volume":"147","author":"Audano","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1093\/hmg\/dds325","article-title":"ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons","volume":"21","author":"Joselin","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1750-3639.1998.tb00137.x","article-title":"Lysosomal and peroxisomal disorders. Recent advances: Introduction","volume":"8","author":"Goebel","year":"1998","journal-title":"Brain Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10545-015-9819-7","article-title":"Peroxisome-mitochondria interplay and disease","volume":"38","author":"Schrader","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_30","unstructured":"Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). Single peroxisomal enzyme deficiencies. The Metabolic & Molecular Bases of Inherited Disease, McGraw-Hill."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1177\/0883073809338327","article-title":"Peroxisomal dysfunction in inflammatory childhood white matter disorders: An unexpected contributor to neuropathology","volume":"24","author":"Singh","year":"2009","journal-title":"J. Child Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1093\/brain\/aws095","article-title":"Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher\u2019s disease","volume":"135","author":"Vitner","year":"2012","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20423","DOI":"10.1074\/jbc.R110.134452","article-title":"Common and uncommon pathogenic cascades in lysosomal storage diseases","volume":"285","author":"Vitner","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.tins.2021.12.004","article-title":"Lysosomal dysfunction in neurodegeneration: Emerging concepts and methods","volume":"45","author":"Udayar","year":"2022","journal-title":"Trends Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.nbd.2011.12.027","article-title":"Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice","volume":"45","author":"Pressey","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1093\/hmg\/ddr019","article-title":"Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease","volume":"20","author":"Vitner","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13024-019-0336-2","article-title":"Glucocerebrosidase and its relevance to Parkinson disease","volume":"14","author":"Do","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuint.2012.10.010","article-title":"Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage","volume":"62","author":"Cleeter","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1080\/15548627.2019.1609847","article-title":"Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels","volume":"15","author":"Tan","year":"2019","journal-title":"Autophagy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"442","DOI":"10.4161\/auto.23344","article-title":"Dysfunctional lysosomal autophagy leads to peroxisomal oxidative burnout and damage during endotoxin-induced stress","volume":"9","author":"Vasko","year":"2013","journal-title":"Autophagy"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.cmet.2014.01.002","article-title":"Peroxisomes: A nexus for lipid metabolism and cellular signaling","volume":"19","author":"Lodhi","year":"2014","journal-title":"Cell Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1074\/jbc.272.10.6245","article-title":"Peroxisomal impairment in Niemann-Pick type C disease","volume":"272","author":"Schedin","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2015.02.019","article-title":"Cholesterol transport through lysosome-peroxisome membrane contacts","volume":"161","author":"Chu","year":"2015","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11731","DOI":"10.1074\/jbc.M412898200","article-title":"Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function","volume":"280","author":"Yu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10190","DOI":"10.1128\/MCB.25.22.10190-10201.2005","article-title":"Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein","volume":"25","author":"Ellis","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.taap.2004.10.001","article-title":"Hepatic mitochondrial glutathione: Transport and role in disease and toxicity","volume":"204","author":"Kaplowitz","year":"2005","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s10545-005-4160-1","article-title":"Glutathione deficiency in patients with mitochondrial disease: Implications for pathogenesis and treatment","volume":"28","author":"Hargreaves","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.bcmd.2008.03.007","article-title":"Plasmalogen levels in Gaucher disease","volume":"41","author":"Moraitou","year":"2008","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ymgme.2004.01.011","article-title":"Reduced activities of respiratory chain enzymes with decreased levels of energy-rich phosphates in fibroblasts","volume":"82","author":"Schmidt","year":"2004","journal-title":"Mol. Genet. Metab."},{"key":"ref_50","unstructured":"Grigoryeva, S. (2018). Secondary coenzyme Q10 deficiencies; Causes and consequence. Coenzyme Q10: Uses, Health and Role in Disease, Nova Science."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/s41598-018-37542-2","article-title":"Plasma coenzyme Q10 status is impaired in selected genetic conditions","volume":"9","author":"Montero","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ymgme.2010.06.018","article-title":"Oxidative stress in Niemann-Pick disease, type C","volume":"101","author":"Fu","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0021-9258(18)97611-8","article-title":"The metabolism of glucocerebrosides. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue","volume":"240","author":"Brady","year":"1965","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.cmet.2013.04.014","article-title":"Mitochondria and quality control defects in amouse model of Gaucher disease\u2013links to Parkinson\u2019s disease","volume":"17","author":"Osellame","year":"2013","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1212\/WNL.0b013e318245f476","article-title":"Penetrance of Parkinson\u2019s disease in glucocerebrosidase gene mutation carriers","volume":"78","author":"Anheim","year":"2012","journal-title":"Neurology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/sj.cdd.4402160","article-title":"Mitochondrial dysfunction in Parkinson\u2019s disease","volume":"14","author":"Schapira","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1093\/hmg\/ddu105","article-title":"Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice","volume":"23","author":"Xu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s12035-013-8394-x","article-title":"\u03b1-Synuclein and Mitochondrial Dysfunction in Parkinson\u2019s Disease","volume":"47","author":"Mullin","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"21490","DOI":"10.1074\/jbc.M113.545749","article-title":"Soluble, prefibrillar alpha-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction","volume":"289","author":"Luth","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.freeradbiomed.2020.04.001","article-title":"Oxidative damage of lysosomes in regulated cell death systems: Pathophysiology and pharmacologic interventions","volume":"157","author":"Nagakannan","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.1016\/S0021-9258(18)93229-1","article-title":"Digestive activity of lysosomes II. The digestion of macromolecular carbohydrates by extracts of rat liver lysosomes","volume":"243","author":"Aronson","year":"1968","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Heaton, R.A., Heales, S., Rahman, K., Sexton, D.W., and Hargreaves, I. (2020). The effect of cellular coenzyme Q(10) deficiency on lysosomal acidification. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061923"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"R315","DOI":"10.1016\/j.cub.2015.02.027","article-title":"Lysosomes","volume":"25","author":"Wartosch","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41392-021-00778-y","article-title":"Targeting lysosomes in human disease: From basic research to clinical applications","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nrd2199","article-title":"How many drug targets are there?","volume":"5","author":"Overington","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Orii, K., Lim, A., Tomatsu, S., Stapleton, M., Suzuki, Y., Simonaro, C.M., Schuchman, E.H., Fukao, T., and Matsumoto, T. (2019). Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II. Diagnostics, 9.","DOI":"10.3390\/diagnostics9040226"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1073\/pnas.0912937107","article-title":"Involvement of the Toll-like receptor 4 pathway and use of TNF-alpha antagonists for treatment of the mucopolysaccharidoses","volume":"107","author":"Simonaro","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Simonaro, C.M., Tomatsu, S., Sikora, T., Kubaski, F., Frohbergh, M., Guevara, J.M., Wang, R.Y., Vera, M., Kang, J.L., and Smith, L.J. (2016). Pentosan polysulfate: Oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153136"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Crivaro, A.N., Mucci, J.M., Bondar, C.M., Ormazabal, M.E., Ceci, R., Simonaro, C., and Rozenfeld, P.A. (2019). Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher disease. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0217780"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ymgme.2011.01.015","article-title":"Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: The positive effect of long-term aspirin treatment","volume":"103","author":"Arfi","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.nbd.2014.03.001","article-title":"Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice","volume":"67","author":"Williams","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/emmm.201202176","article-title":"Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease","volume":"5","author":"Spampanato","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15089","DOI":"10.1038\/s41598-017-15352-2","article-title":"AAV-mediated transcription factor EB (TFEB) gene delivery ameliorates muscle pathology and function in the murine model of Pompe Disease","volume":"7","author":"Gatto","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ceca.2011.03.010","article-title":"Lysosomal Ca(2+) homeostasis: Role in pathogenesis of lysosomal storage diseases","volume":"50","author":"Platt","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.expneurol.2012.07.013","article-title":"Oxidative stress as a therapeutic target in globoid cell leukodystrophy","volume":"237","author":"Qin","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/jimd.12428","article-title":"Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2\/3 trial of a novel treatment","volume":"44","author":"Mengel","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"10903","DOI":"10.1038\/srep10903","article-title":"Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant \u03b2-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease","volume":"5","author":"Cordero","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.redox.2016.11.010","article-title":"Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease","volume":"11","author":"Torres","year":"2017","journal-title":"Redox Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1046\/j.1471-4159.2003.01941.x","article-title":"Molecular mechanism of psychosine-induced cell death in human oligodendrocyte cell line","volume":"86","author":"Haq","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e1529","DOI":"10.1038\/cddis.2014.483","article-title":"Role of extracellular calcium and mitochondrial oxygen species in psychosine-induced oligodendrocyte cell death","volume":"5","author":"Voccoli","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1111\/j.1460-9568.2005.03889.x","article-title":"A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson\u2019s disease","volume":"21","author":"Offen","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/jcph.1008","article-title":"Repeated-Dose Oral N-Acetylcysteine in Parkinson\u2019s Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress","volume":"58","author":"Coles","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3508","DOI":"10.1093\/hmg\/ddt206","article-title":"Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann-Pick disease, type C1","volume":"22","author":"Fu","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1474-9726.2008.00407.x","article-title":"Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity","volume":"7","author":"Cerqueira","year":"2008","journal-title":"Aging Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.tibs.2016.09.001","article-title":"Calcium at the Center of Cell Signaling: Interplay between endoplasmic reticulum, mitochondria, and lysosomes","volume":"41","author":"Raffaello","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB","volume":"17","author":"Medina","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ymgme.2008.12.008","article-title":"Diltiazem, a L-type Ca(2+) channel blocker, also acts as a pharmacological chaperone in Gaucher patient cells","volume":"96","author":"Rigat","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/jimd.12235","article-title":"The definition of neuronopathic Gaucher disease","volume":"43","author":"Schiffmann","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e10616","DOI":"10.7554\/eLife.10616","article-title":"Intracellular sphingosine releases calcium from lysosomes","volume":"4","author":"Haberkant","year":"2015","journal-title":"Elife"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.devcel.2011.07.016","article-title":"Transcriptional activation of lysosomal exocytosis promotes cellular clearance","volume":"21","author":"Medina","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"E1817","DOI":"10.1073\/pnas.1305623110","article-title":"TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity","volume":"110","author":"Decressac","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.1038\/emboj.2011.257","article-title":"Regulation of TFEB and V-ATPases by mTORC1","volume":"30","author":"Schwartz","year":"2011","journal-title":"EMBO J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1111\/j.1471-4159.2006.03733.x","article-title":"Neuronal cell death caused by inhibition of intracellular cholesterol trafficking is caspase dependent and associated with activation of the mitochondrial apoptosis pathway","volume":"97","author":"Huang","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.bbrc.2007.12.187","article-title":"Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis","volume":"367","author":"Takamura","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"13761","DOI":"10.1523\/JNEUROSCI.4246-09.2009","article-title":"A nanomedicine transports a peptide caspase-3 inhibitor across the blood-brain barrier and provides neuroprotection","volume":"29","author":"Karatas","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"87","DOI":"10.14348\/molcells.2016.2318","article-title":"Sirt1 and the mitochondria","volume":"39","author":"Tang","year":"2016","journal-title":"Mol. Cells"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1093\/hmg\/ddq555","article-title":"Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: Partial rescue by resveratrol","volume":"20","author":"Wei","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1111\/j.1471-4159.2007.05194.x","article-title":"The GSK3 hypothesis of Alzheimer\u2019s disease","volume":"104","author":"Hooper","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.mcn.2007.08.004","article-title":"Serotonin stimulates mitochondrial transport in hippocampal neurons","volume":"36","author":"Chen","year":"2007","journal-title":"Mol. Cell Neurosci."},{"key":"ref_100","first-page":"32","article-title":"GSK-3 inhibitors: Preclinical and clinical focus on CNS","volume":"4","author":"Martinez","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"10048","DOI":"10.1523\/JNEUROSCI.0217-13.2013","article-title":"The sphingolipid psychosine inhibits fast axonal transport in Krabbe disease by activation of GSK3beta and deregulation of molecular motors","volume":"33","author":"Castelvetri","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ymthe.2006.08.009","article-title":"Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease","volume":"14","author":"Fukuda","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e2331","DOI":"10.1038\/cddis.2016.231","article-title":"Glial degeneration with oxidative damage drives neuronal demise in MPSII disease","volume":"7","author":"Zalfa","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Viana, G.M., Priestman, D.A., Platt, F.M.K., Tomatsu, S., and Pshezhetsky, A.V. (2020). Brain pathology in mucopolysaccharidoses (MPS) patients with neurological forms. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020396"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Heon-Roberts, R., Nguyen, A.L.A., and Pshezhetsky, A.V. (2020). Molecular bases of neurodegeneration and cognitive decline, the major burden of Sanfilippo disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020344"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.cca.2007.09.008","article-title":"Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy","volume":"387","author":"Pereira","year":"2008","journal-title":"Clin. Chim. Acta"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.bbadis.2015.02.004","article-title":"Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy","volume":"1852","author":"Donida","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ymgme.2011.02.016","article-title":"Oxidative stress in patients with mucopolysaccharidosis type II before and during enzyme replacement therapy","volume":"103","author":"Filippon","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.brainres.2009.03.071","article-title":"Mucopolysaccharidosis IIIB: Oxidative damage and cytotoxic cell involvement in the neuronal pathogenesis","volume":"1279","author":"Villani","year":"2009","journal-title":"Brain Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.2353\/ajpath.2010.100447","article-title":"Storage vesicles in neurons are related to Golgi complex alterations in mucopolysaccharidosis IIIB","volume":"177","author":"Vitry","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_111","first-page":"e142073","article-title":"Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission","volume":"6","author":"Bose","year":"2021","journal-title":"JCI Insight"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1093\/hmg\/ddr610","article-title":"Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases","volume":"21","author":"Saide","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1093\/hmg\/ddm289","article-title":"A block of autophagy in lysosomal storage disorders","volume":"17","author":"Settembre","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"33684","DOI":"10.1038\/srep33684","article-title":"BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases","volume":"6","author":"Zhong","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/j.1471-4159.2005.03534.x","article-title":"Defective calcium homeostasis in the cerebellum in a mouse model of Niemann-Pick A disease","volume":"95","author":"Ginzburg","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.celrep.2013.10.042","article-title":"Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease","volume":"5","author":"Sarkar","year":"2013","journal-title":"Cell Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/ncomms1735","article-title":"Lipid storage disorders block lysosomal trafficking by inhibiting TRP channel and calcium release","volume":"3","author":"Shen","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1086\/320599","article-title":"Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1","volume":"68","author":"Sun","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/jnr.23804","article-title":"Neuroimmune mechanisms in Krabbe\u2019s disease","volume":"94","author":"Potter","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"R119","DOI":"10.1093\/hmg\/ddy155","article-title":"The pathogenesis of lysosomal storage disorders: Beyond the engorgement of lysosomes to abnormal development and neuroinflammation","volume":"27","author":"Fiorenza","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s12974-019-1672-4","article-title":"Unique molecular signature in mucolipidosis type IV microglia","volume":"16","author":"Cougnoux","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Kennedy, B.E., LeBlanc, V.G., Mailman, T.M., Fice, D., Burton, I., Karakach, T.K., and Karten, B. (2013). Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick type C1-deficient murine brain. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082685"},{"key":"ref_123","first-page":"7031","article-title":"Neuronopathic Gaucher disease: Dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model","volume":"24","author":"Dasgupta","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.nbd.2014.02.012","article-title":"Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe\u2019s disease","volume":"66","author":"Teixeira","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.bbrc.2006.02.131","article-title":"Dysfunction of peroxisomes in twitcher mice brain: A possible mechanism of psychosine-induced disease","volume":"343","author":"Haq","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0006-8993(85)90099-X","article-title":"Altered patterns of evoked synaptic activity in cortical pyramidal neurons in feline ganglioside storage disease","volume":"339","author":"Karabelas","year":"1985","journal-title":"Brain Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/0006-8993(80)90627-7","article-title":"Intracellular recording and HRP-staining of cortical neurons in feline ganglioside storage disease","volume":"181","author":"Purpura","year":"1980","journal-title":"Brain Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ymgme.2014.11.015","article-title":"Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses","volume":"114","author":"Utz","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.molcel.2009.10.021","article-title":"GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis","volume":"36","author":"Sano","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1097\/NEN.0b013e3181942cf0","article-title":"Neuropathology of the Mcoln1-\/-knockout mouse model of mucolipidosis type IV","volume":"68","author":"Micsenyi","year":"2009","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Jezela-Stanek, A., Ciara, E., and Stepien, K.M. (2020). Neuropathophysiology, Genetic Profile, and Clinical Manifestation of Mucolipidosis IV-A Review and Case Series. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124564"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2051-5960-2-20","article-title":"Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice","volume":"2","author":"Nelson","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/glia.22962","article-title":"Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease","volume":"64","author":"Groh","year":"2016","journal-title":"Glia"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Uusi-Rauva, K., Blom, T., von Schantz-Fant, C., Blom, T., Jalanko, A., Kytt\u00e4l\u00e4, and A (2017). Induced pluripotent stem cells derived from a CLN5 patient manifest phenotypic characteristics of neuronal ceroid lipofuscinoses. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050955"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ceca.2011.08.004","article-title":"Deficient mitochondrial Ca(2+) buffering in the Cln8(mnd) mouse model of neuronal ceroid lipofuscinosis","volume":"50","author":"Kolikova","year":"2011","journal-title":"Cell Calcium"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1080\/15548627.2015.1009779","article-title":"Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease","volume":"11","author":"Lim","year":"2015","journal-title":"Autophagy"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10573\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:29:58Z","timestamp":1760142598000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,12]]},"references-count":136,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810573"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810573","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,12]]}}}