Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65170710.31857/S0869813923110080GNDEZVREVIEW AND PROBLEM ARTICLESОБЗОРНЫЕ И ПРОБЛЕМНЫЕ СТАТЬИExperimental Models of CNS Deficits in Lysosomal Storage DiseasesЭкспериментальные модели нарушений ЦНС при развитии болезней лизосомального накопленияLebedevA. S.ЛебедевА. С.avkalueff@gmail.comKotovaM. M.КотоваМ. М.avkalueff@gmail.comKolesnikovaT. O.КолесниковаТ. О.avkalueff@gmail.comGalstyanD. S.ГалстянД. С.avkalueff@gmail.comKalueffA. V.КалуевА. В.avkalueff@gmail.comWorld-class Scientific Research Center “Center of Personalized Medicine”, Almazov National Medical Research Center, Ministry of Healthcare of Russian FederationНаучный центр мирового уровня “Центр персонализированной медицины”, Национальный медицинский исследовательский центр им. В.А. Алмазова МЗ РФNeurobiology Department, Research Center for Genetics and Life Sciences, Sirius University of Science and TechnologyНаправление “Нейробиология”, Научный центр генетики и наук о жизни, Научно-технологический университет “Сириус”Institute of Translational Biomedicine, St. Petersburg State UniversityИнститут трансляционной биомедицины, Санкт-Петербургский государственный университетGranov Russian Scientific Center for Radiology and Surgical Technologies, Ministry of Healthcare of Russian FederationРоссийский научный центр радиологии и хирургических технологий им. акад. А.М. Гранова МЗ РФUral Federal UniversityУральский федеральный университетScientific Research Institute of Neurosciences and MedicineНИИ нейронаук и медицины01112023109111567158301022025Copyright ©; 2023, А.С. Лебедев, М.М. Котова, Т.О. Колесникова, Д.С. Галстян, А.В. КалуевCopyright ©; 2023, А.С. Лебедев, М.М. Котова, Т.О. Колесникова, Д.С. Галстян, А.В. Калуев2023А.С. Лебедев, М.М. Котова, Т.О. Колесникова, Д.С. Галстян, А.В. КалуевА.С. Лебедев, М.М. Котова, Т.О. Колесникова, Д.С. Галстян, А.В. Калуевhttps://transsyst.ru/0869-8139/article/view/651707

Lysosomal storage diseases are characterized by enzyme deficiency in the lysosomal appar-atus of the cell, triggering a pathological accumulation of undigested cellular material (proteins, lipids or carbohydrates) and tissue damage. Clinically and etiologically dive-rse, this group includes over 70 presently recognized hereditary conditions with no known effective therapy. Thus, the search for therapeutic strategies directed at these disorders represents an urgent unmet biomedical task, also necessitating the use of appropriate and valid experimental (animal) models. Here, we discuss the existing models of lysosomal storage diseases and the applicability of rodent and zebrafish as model organisms for probing these diseases.

Болезни лизосомального накопления (БЛН) представляют собой группу орфанных заболеваний, вызванных недостаточностью ферментов лизосом, в результате чего происходит накопление непереваренного материала в клетках и повреждаются ткани. Различаясь по типу накопленного материала (белки, липиды или углеводы), БЛН также чрезвычайно разнообразны по своей клинической картине. При этом наиболее частым проявлением БЛН является повреждение мозга, приводящее к различным неврологическим дисфункциям. К настоящему моменту известно более 70 БЛН, для которых практически не существует эффективной терапии. Настоящий обзор посвящен обсуждению существующих БЛН, их последствий для мозга, а также значению экспериментальных (животных) моделей для выяснения механизмов их патогенеза и поиска новых средств терапии.

lysosomal storage diseaseslysosomesenzymopathiesCNS disordersanimal modelsболезни лизосомального накоплениялизосомыферментопатиинарушения ЦНСживотные моделиPlatt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ (2018) Lysosomal storage diseases. Nat Rev Dis Primer 4: 27. https://doi.org/10.1038/s41572-018-0025-4Marques ARA, Saftig P (2019) Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases. J Cell Sci 132: jcs221739. https://doi.org/10.1242/jcs.221739Martina JA, Raben N, Puertollano R (2020) SnapShot: Lysosomal Storage Diseases. Cell 180: 602–602. https://doi.org/10.1016/j.cell.2020.01.017McKenna MC, Schuck PF, Ferreira GC (2019) Fundamentals of CNS energy metabolism and alterations in lysosomal storage diseases. J Neurochem 148: 590–599. https://doi.org/10.1111/jnc.14577Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C, Billette de Villemeur T, Berger MG (2017) A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci 18: 441. https://doi.org/10.3390/ijms18020441Rosenbloom BE, Weinreb NJ (2013) Gaucher disease: a comprehensive review. Crit Rev Oncog 18: 163–175. https://doi.org/10.1615/critrevoncog.2013006060Bradbury AM, Bongarzone ER, Sands MS (2021) Krabbe disease: New hope for an old disease. Neurosci Lett 752: 135841. https://doi.org/10.1016/j.neulet.2021.135841Chan B, Adam DN (2018) A Review of Fabry Disease. Skin Ther Lett 23: 4–6.Mahmud HM (2014) Fabry’s disease – a comprehensive review on pathogenesis, diagnosis and treatment. J Pak Med Assoc 64: 189–194.Dasouki M, Jawdat O, Almadhoun O, Pasnoor M, McVey AL, Abuzinadah A, Herbelin L, Barohn RJ, Dimachkie MM (2014) Pompe disease: literature review and case series. Neurol Clin 32: 751–776. https://doi.org/10.1016/j.ncl.2014.04.010Kohler L, Puertollano R, Raben N (2018) Pompe Disease: From Basic Science to Therapy. Neurother J 15: 928–942. https://doi.org/10.1007/s13311-018-0655-yNita DA, Mole SE, Minassian BA (2016) Neuronal ceroid lipofuscinoses. Epileptic Disord Int Epilepsy J 18: 73–88. https://doi.org/10.1684/epd.2016.0844Parini R, Deodato F (2020) Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int J Mol Sci 21: 2975. https://doi.org/10.3390/ijms21082975Tomatsu S, Alméciga-Díaz CJ, Montaño AM, Yabe H, Tanaka A, Dung VC, Giugliani R, Kubaski F, Mason RW, Yasuda E, Sawamoto K, Mackenzie W, Suzuki Y, Orii KE, Barrera LA, Sly WS, Orii T (2015) Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab 114: 94–109. https://doi.org/10.1016/j.ymgme.2014.12.001van Rappard DF, Boelens JJ, Wolf NI (2015) Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab 29: 261–273. https://doi.org/10.1016/j.beem.2014.10.001Hess B, Saftig P, Hartmann D, Coenen R, Lüllmann-Rauch R, Goebel HH, Evers M, von Figura K, D’Hooge R, Nagels G, De Deyn P, Peters C, Gieselmann V (1996) Phenotype of arylsulfatase A-deficient mice: relationship to human metachromatic leukodystrophy. Proc Natl Acad Sci U S A 93: 14821–14826. https://doi.org/10.1073/pnas.93.25.14821Cenacchi G, Papa V, Pegoraro V, Marozzo R, Fanin M, Angelini C (2020) Review: Danon disease: Review of natural history and recent advances. Neuropathol Appl Neurobiol 46: 303–322. https://doi.org/10.1111/nan.12587Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M (2004) Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 34: 236–242. https://doi.org/10.1111/j.1365-2362.2004.01309.xLantos JD (2011) Dangerous and expensive screening and treatment for rare childhood diseases: the case of Krabbe disease. Dev Disabil Res Rev 17: 15–18. https://doi.org/10.1002/ddrr.133Hult M, Darin N, von Döbeln U, Månsson J-E (2014) Epidemiology of lysosomal storage diseases in Sweden. Acta Paediatr (103): 1258–1263. https://doi.org/10.1111/apa.12807Zlotogora J (1997) Autosomal recessive diseases among Palestinian Arabs. J Med Genet 34: 765–766. https://doi.org/10.1136/jmg.34.9.765Ausems MG, Verbiest J, Hermans MP, Kroos MA, Beemer FA, Wokke JH, Sandkuijl LA, Reuser AJ, van der Ploeg AT (1999) Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 7: 713–716. https://doi.org/10.1038/sj.ejhg.5200367De Jesus Rojas W, Young LR (2020) Hermansky-Pudlak Syndrome. Semin Respir Crit Care Med 41: 238–246. https://doi.org/10.1055/s-0040-1708088Aronson NN (1999) Aspartylglycosaminuria: biochemistry and molecular biology. Biochim Biophys Acta 1455: 139–154. https://doi.org/10.1016/s0925-4439(99)00076-9Chan B, Adam DN (2018) A Review of Fabry Disease. Skin Ther Lett 23: 4–6.Tylki-Szymańska A (2014) Mucopolysaccharidosis type II, Hunter’s syndrome. Pediatr Endocrinol Rev 12 Suppl 1: 107–113.Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML (2015) Sanfilippo syndrome: Overall review. Pediatr Int 57: 331–338. https://doi.org/10.1111/ped.12636Beard H, Luck AJ, Hassiotis S, King B, Trim PJ, Snel MF, Hopwood JJ, Hemsley KM (2015) Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice. Mol Genet Metab 115: 33–40. https://doi.org/10.1016/j.ymgme.2015.03.002Zemoura K, Ralvenius WT, Malherbe P, Benke D (2016) The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice. Neuropharmacology 108: 172–178. https://doi.org/10.1016/j.neuropharm.2016.04.028Goo MS, Sancho L, Slepak N, Boassa D, Deerinck TJ, Ellisman MH, Bloodgood BL, Patrick GN (2017) Activity-dependent trafficking of lysosomes in dendrites and dendritic spines. J Cell Biol 216: 2499–2513. https://doi.org/10.1083/jcb.201704068Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman AB, Aschner M (2011) Role of astrocytes in brain function and disease. Toxicol Pathol 39: 115–123. https://doi.org/10.1177/0192623310385254D’Arcangelo G, Grossi D, De Chiara G, de Stefano MC, Cortese G, Citro G, Rufini S, Tancredi V, Merlo D, Frank C (2011) Glutamatergic neurotransmission in a mouse model of Niemann-Pick type C disease. Brain Res 1396: 11–19. https://doi.org/10.1016/j.brainres.2011.04.020Vance JE (2006) Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett 580: 5518–5524. https://doi.org/10.1016/j.febslet.2006.06.008Lou HO, Reske-Nielsen E (1971) the central nervous system in Fabry’s disease. A clinical, pathological, and biochemical investigation. Arch Neurol 25: 351–359. https://doi.org/10.1001/archneur.1971.00490040077009Tybulewicz VL, Tremblay ML, LaMarca ME, Willemsen R, Stubblefield BK, Winfield S, Zablocka B, Sidransky E, Martin BM, Huang SP (1992) Animal model of Gaucher’s disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357: 407–410. https://doi.org/10.1038/357407a0Xu Y-H, Quinn B, Witte D, Grabowski GA (2003) Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. Am J Pathol 163: 2093–2101. https://doi.org/10.1016/s0002-9440(10)63566-3Enquist IB, Lo Bianco C, Ooka A, Nilsson E, Månsson J-E, Ehinger M, Richter J, Brady RO, Kirik D, Karlsson S (2007) Murine models of acute neuronopathic Gaucher disease. Proc Natl Acad Sci U S A 104: 17483–17488. https://doi.org/10.1073/pnas.0708086104Kobayashi T, Yamanaka T, Jacobs JM, Teixeira F, Suzuki K (1980) The Twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease). Brain Res 202: 479–483. https://doi.org/10.1016/0006-8993(80)90159-6Duchen LW, Eicher EM, Jacobs JM, Scaravilli F, Teixeira F (1980) Hereditary leucodystrophy in the mouse: the new mutant twitcher. Brain J Neurol 103: 695–710. https://doi.org/10.1093/brain/103.3.695Bijvoet AG, van de Kamp EH, Kroos MA, Ding JH, Yang BZ, Visser P, Bakker CE, Verbeet MP, Oostra BA, Reuser AJ, van der Ploeg AT (1998) Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease. Hum Mol Genet 7. https://doi.org/10.1093/hmg/7.1.53Raben N, Nagaraju K, Lee E, Kessler P, Byrne B, Lee L, LaMarca M, King C, Ward J, Sauer B, Plotz P (1998) Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem 273. https://doi.org/10.1074/jbc.273.30.19086Rothaug M, Stroobants S, Schweizer M, Peters J, Zunke F, Allerding M, D’Hooge R, Saftig P, Blanz J (2015) LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease. Acta Neuropathol Commun 3. https://doi.org/10.1186/s40478-014-0182-yGupta P, Soyombo AA, Atashband A, Wisniewski KE, Shelton JM, Richardson JA, Hammer RE, Hofmann SL (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci U S A 98: 13566–13571. https://doi.org/10.1073/pnas.251485198Katz ML, Johnson GS (2001) Mouse gene knockout models for the CLN2 and CLN3 forms of ceroid lipofuscinosis. Eur J Paediatr Neurol 5: 109–114. https://doi.org/10.1053/ejpn.2000.0445Eliason SL, Stein CS, Mao Q, Tecedor L, Ding S-L, Gaines DM, Davidson BL (2007) A knock-in reporter model of Batten disease. J Neurosci Off J Soc Neurosci 27: 9826–9834. https://doi.org/10.1523/JNEUROSCI.1710-07.2007Kalueff AV, Stewart AM, Gerlai R (2014) Zebrafish as an emerging model for studying complex brain disorders. Trends Pharmacol Sci 35: 63–75. https://doi.org/10.1016/j.tips.2013.12.002Zhang T, Peterson RT (2020) Modeling Lysosomal Storage Diseases in the Zebrafish. Front Mol Biosci 7: 82. https://doi.org/10.3389/fmolb.2020.00082Zancan I, Bellesso S, Costa R, Salvalaio M, Stroppiano M, Hammond C, Argenton F, Filocamo M, Moro E (2015) Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling. Hum Mol Genet 24: 1280–1294. https://doi.org/10.1093/hmg/ddu538Zizioli D, Guarienti M, Tobia C, Gariano G, Borsani G, Bresciani R, Ronca R, Giacopuzzi E, Preti A, Gaudenzi G, Belleri M, Di Salle E, Fabrias G, Casas J, Ribatti D, Monti E, Presta M (2014) Molecular cloning and knockdown of galactocerebrosidase in zebrafish: new insights into the pathogenesis of Krabbe’s disease. Biochim Biophys Acta 1842: 665–675. https://doi.org/10.1016/j.bbadis.2014.01.008Wu J, Yang Y, Sun C, Sun S, Li Q, Yao Y, Fei F, Lu L, Chang Z, Zhang W, Wang X, Luo F (2017) Disruption of the gaa Gene in Zebrafish Fails to Generate the Phenotype of Classical Pompe Disease. DNA Cell Biol 36: 10–17. https://doi.org/10.1089/dna.2016.3459Dvornikov AV, Wang M, Yang J, Zhu P, Le T, Lin X, Cao H, Xu X (2019) Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy. J Mol Cell Cardiol 133: 199–208. https://doi.org/10.1016/j.yjmcc.2019.06.013Mahmood F, Fu S, Cooke J, Wilson SW, Cooper JD, Russell C (2013) A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain J Neurol 136: 1488–1507. https://doi.org/10.1093/brain/awt043Wager K, Zdebik AA, Fu S, Cooper JD, Harvey RJ, Russell C (2016) Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease). PloS One 11: e0157365. https://doi.org/10.1371/journal.pone.0157365Rodrigues de Souza I, Wilke Sivek T, Vaz de Oliveira JB, Di Pietro Micali Canavez A, de Albuquerque Vita N, Cigaran Schuck D, Rodrigues de Souza I, Cestari MM, Lorencini M, Leme DM (2023) Cytotoxicity Assays with Zebrafish Cell Lines. J Vis Exp. https://doi.org/10.3791/64860Patton EE, Zon LI, Langenau DM (2021) Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov 20: 611–628. https://doi.org/10.1038/s41573-021-00210-8Zhang T, Alonzo I, Stubben C, Geng Y, Herdman C, Chandler N, Doane KP, Pluimer BR, Trauger SA, Peterson RT (2023) A zebrafish model of combined saposin deficiency identifies acid sphingomyelinase as a potential therapeutic target. Dis Model Mech 16: dmm049995. https://doi.org/10.1242/dmm.049995Zhang T, Peterson RT (2020) Modeling Lysosomal Storage Diseases in the Zebrafish. Front Mol Biosci 7: 82. https://doi.org/10.3389/fmolb.2020.00082Marza E, Barthe C, André M, Villeneuve L, Hélou C, Babin PJ (2005) Developmental expression and nutritional regulation of a zebrafish gene homologous to mammalian microsomal triglyceride transfer protein large subunit. Dev Dyn 232: 506–518. https://doi.org/10.1002/dvdy.20251Clifton JD, Lucumi E, Myers MC, Napper A, Hama K, Farber SA, Smith AB, Huryn DM, Diamond SL, Pack M (2010) Identification of novel inhibitors of dietary lipid absorption using zebrafish. PloS One 5: e12386. https://doi.org/10.1371/journal.pone.0012386Pickart MA, Klee EW, Nielsen AL, Sivasubbu S, Mendenhall EM, Bill BR, Chen E, Eckfeldt CE, Knowlton M, Robu ME, Larson JD, Deng Y, Schimmenti LA, Ellis LBM, Verfaillie CM, Hammerschmidt M, Farber SA, Ekker SC (2006) Genome-wide reverse genetics framework to identify novel functions of the vertebrate secretome. PloS One 1: e104. https://doi.org/10.1371/journal.pone.0000104Stoletov K, Fang L, Choi S-H, Hartvigsen K, Hansen LF, Hall C, Pattison J, Juliano J, Miller ER, Almazan F, Crosier P, Witztum JL, Klemke RL, Miller YI (2009) Vascular lipid accumulation, lipoprotein oxidation, and macrophage lipid uptake in hypercholesterolemic zebrafish. Circ Res 104: 952–960. https://doi.org/10.1161/CIRCRESAHA.108.189803Walker MT, Montell C (2016) Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation. Hum Mol Genet 25: 2752–2761. https://doi.org/10.1093/hmg/ddw132Venkatachalam K, Long AA, Elsaesser R, Nikolaeva D, Broadie K, Montell C (2008) Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135: 838–851. https://doi.org/10.1016/j.cell.2008.09.041Jin W, Dai Y, Li F, Zhu L, Huang Z, Liu W, Li J, Zhang M, Du J, Zhang W, Wen Z (2019) Dysregulation of Microglial Function Contributes to Neuronal Impairment in Mcoln1a-Deficient Zebrafish. Science 13: 391–401. https://doi.org/10.1016/j.isci.2019.02.031Kiselyov K, Jennigs JJ, Rbaibi Y, Chu CT (2007) Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy 3: 259–262. https://doi.org/10.4161/auto.3906Jolly RD, Brown S, Das AM, Walkley SU (2002) Mitochondrial dysfunction in the neuronal ceroid-lipofuscinoses (Batten disease). Neurochem Int 40: 565–571. https://doi.org/10.1016/s0197-0186(01)00128-0Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C, Medina D, de Pablo R, Tacchetti C, Rubinsztein DC, Ballabio A (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17: 119–129. https://doi.org/10.1093/hmg/ddm289Takamura A, Higaki K, Kajimaki K, Otsuka S, Ninomiya H, Matsuda J, Ohno K, Suzuki Y, Nanba E (2008) Enhanced autophagy and mitochondrial aberrations in murine G(M1)-gangliosidosis. Biochem Biophys Res Commun 367: 616–622. https://doi.org/10.1016/j.bbrc.2007.12.187de la Mata M, Cotán D, Oropesa-Ávila M, Garrido-Maraver J, Cordero MD, Villanueva Paz M, Delgado Pavón A, Alcocer-Gómez E, de Lavera I, Ybot-González P, Paula Zaderenko A, Ortiz Mellet C, García Fernández JM, Sánchez-Alcázar JA (2015) Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant β-Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease. Sci Rep 5: 10903. https://doi.org/10.1038/srep10903Plucińska G, Paquet D, Hruscha A, Godinho L, Haass C, Schmid B, Misgeld T (2012) In vivo imaging of disease-related mitochondrial dynamics in a vertebrate model system. J Neurosci 32: 16203–16212. https://doi.org/10.1523/JNEUROSCI.1327-12.2012Riboldi GM, Di Fonzo AB (2019) GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches. Cells 8: 364. https://doi.org/10.3390/cells8040364Schmidt R, Strähle U, Scholpp S (2013) Neurogenesis in zebrafish - from embryo to adult. Neural Develop 8: 3. https://doi.org/10.1186/1749-8104-8-3Meijer AH, Aerts JM (2016) Linking Smokers’ Susceptibility to Tuberculosis with Lysosomal Storage Disorders. Dev Cell 37: 112–113. https://doi.org/10.1016/j.devcel.2016.04.004Su Q, Schröder SP, Lelieveld LT, Ferraz MJ, Verhoek M, Boot RG, Overkleeft HS, Aerts JMFG, Artola M, Kuo C-L (2021) Xylose-Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase. Chembiochem Eur J Chem Biol 22: 3090–3098. https://doi.org/10.1002/cbic.202100396Li H, Pei W, Vergarajauregui S, Zerfas PM, Raben N, Burgess SM, Puertollano R (2017) Novel degenerative and developmental defects in a zebrafish model of mucolipidosis type IV. Hum Mol Genet 26: 2701–2718. https://doi.org/10.1093/hmg/ddx158Platt FM (2018) Emptying the stores: lysosomal diseases and therapeutic strategies. Nat Rev Drug Discov 17: 133–150. https://doi.org/10.1038/nrd.2017.214Klein AD, Ferreira N-S, Ben-Dor S, Duan J, Hardy J, Cox TM, Merrill AH, Futerman AH (2016) Identification of Modifier Genes in a Mouse Model of Gaucher Disease. Cell Rep 16: 2546–2553. https://doi.org/10.1016/j.celrep.2016.07.085Ogawa Y, Sano T, Irisa M, Kodama T, Saito T, Furusawa E, Kaizu K, Yanagi Y, Tsukimura T, Togawa T, Yamanaka S, Itoh K, Sakuraba H, Oishi K (2017) FcRγ-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice. Sci Rep 7: 40518. https://doi.org/10.1038/srep40518Udayar V, Chen Y, Sidransky E, Jagasia R (2022) Lysosomal dysfunction in neurodegeneration: emerging concepts and methods. Trends Neurosci 45: 184–199. https://doi.org/10.1016/j.tins.2021.12.004Li B, Wang F, Schall N, Muller S (2018) Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide. J Autoimmun 90: 132–145. https://doi.org/10.1016/j.jaut.2018.02.005Mathai BJ, Meijer AH, Simonsen A (2017) Studying Autophagy in Zebrafish. Cells 6: 21. https://doi.org/10.3390/cells6030021Tseng W-C, Johnson Escauriza AJ, Tsai-Morris C-H, Feldman B, Dale RK, Wassif CA, Porter FD (2021) The role of Niemann-Pick type C2 in zebrafish embryonic development. Dev Camb Engl 148: dev194258. https://doi.org/10.1242/dev.194258Bonam SR, Wang F, Muller S (2019) Lysosomes as a therapeutic target. Nat Rev Drug Discov 18: 923–948. https://doi.org/10.1038/s41573-019-0036-1