Accessible Requires Authentication Published by De Gruyter January 9, 2020

The function of lysosomes and their role in Parkinson’s disease

Friederike Zunke ORCID logo
From the journal Neuroforum

Abstract

Lysosomes are cellular organelles that are important for the degradation and recycling of various biomolecules. Specialized lysosomal membrane proteins, as well as soluble enzymes, are important for the efficient turn-over of lysosomal substrates. A deficiency in the degradative capacity of lysosomes leads to severe pathologies referred to as lysosomal storage disorders. There is increasing evidence for the importance of lysosomal function in neurodegenerative disorders, including Parkinson’s disease. One reason for this might be the vulnerability of neuronal cells. Since neurons do not undergo further cell division, non-degraded substrates accumulate in aging cells, causing a buildup of toxicity. Recent genomic screenings identified a number of lysosome-associated genes as potential risk factors for Parkinson’s disease, which are discussed in this review. Moreover, it is outlined how targeting lysosomal function might help in developing novel therapeutic strategies.

Zusammenfassung

Lysosomen sind membranumschlossene Zellorganelle, in denen lösliche Enzyme für den Abbau sowie das Recycling intrazellulärer als auch extrazellulärer Biomoleküle sorgen. Kommt es dagegen zu einer unvollständigen Degradation hat das schwerwiegende pathologische Konsequenzen und führt zu sogenannten lysosomalen Speichererkrankungen. Forschungsergebnisse der letzten Jahre deuten auf einen Zusammenhang zwischen lysosomaler Dysfunktion und dem Krankheitsverlauf neurodegenerativen Erkrankungen hin – so wie zum Beispiel beim Morbus Parkinson. Eine mögliche Erklärung hierfür ist, dass neuronale Zellen keine Zellteilung mehr durchlaufen und sich so über die Zeit lysosomale Substrate anhäufen. Interessanterweise zeigen genetische Untersuchungen von Parkinson Patienten eine Anhäufung lysosomaler Gene, welche als Risikofaktoren für die Erkrankung beschrieben und in diesem Review behandelt werden. Des Weiteren wird diskutiert, welche Rolle Lysosomen bei der Entwicklung neuartiger Therapien zur Behandlung der Parkinson Erkrankung spielen können.

Funding

Funder Name: Deutsche Forschungsgemeinschaft, Funder Id: http://dx.doi.org/10.13039/501100001659, Grant Number: 125440785—SFB 877, project B11

References

Baba, M., Nakajo, S., Tu, P.H., Tomita, T., Nakaya, K., Lee, V.M., Trojanowski, J.Q., and Iwatsubo, T. (1998). Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884. Search in Google Scholar

Bainton, D.F. (1981). The discovery of lysosomes. J. Cell Biol. 91, 66s–76 s. Search in Google Scholar

Bar-On, P., Rockenstein, E., Adame, A., Ho, G., Hashimoto, M., and Masliah, E. (2006). Effects of the cholesterol-lowering compound methyl-β-cyclodextrin in models of α-synucleinopathy. J. Neurochem. 98, 1032–1045. Search in Google Scholar

Beavan, M.S., and Schapira, A.H. (2013). Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann. Med. 45, 511–521. Search in Google Scholar

Beck, M. (2018). Treatment strategies for lysosomal storage disorders. Dev. Med. Child Neurol. 60, 13–18. Search in Google Scholar

Bennett, M.J., and Rakheja, D. (2013). The neuronal ceroid-lipofuscinoses. Dev. Disabil. Res. Rev. 17, 254–259. Search in Google Scholar

Blanz, J., Zunke, F., Markmann, S., Damme, M., Braulke, T., Saftig, P., and Schwake, M. (2015). Mannose 6-phosphate-independent Lysosomal Sorting of LIMP-2. Traffic 16, 1127–1136. Search in Google Scholar

Bosco, D.A., Fowler, D.M., Zhang, Q., Nieva, J., Powers, E.T., Wentworth, P., Jr., Lerner, R.A., and Kelly, J.W. (2006). Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization. Nat. Chem. Biol. 2, 249–253. Search in Google Scholar

Braak, H., and Del Tredici, K. (2017). Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J. Parkinsons Dis. 7, S71-S85. Search in Google Scholar

Chang, D., Nalls, M.A., Hallgrimsdottir, I.B., Hunkapiller, J., van der Brug, M., Cai, F., International Parkinson’s Disease Genomics Consortium, 23andMe Research Team, et al. (2017). A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516. Search in Google Scholar

Chaudhuri, K.R., Healy, D.G., Schapira, A.H., and National Institute for Clinical Excellence (2006). Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 5, 235–245. Search in Google Scholar

Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., and Sulzer, D. (2004). Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295. Search in Google Scholar

Cullen, V., Lindfors, M., Ng, J., Paetau, A., Swinton, E., Kolodziej, P., Boston, H., Saftig, P., et al. (2009). Cathepsin D expression level affects α-synuclein processing, aggregation, and toxicity in vivo. Mol. Brain 2, 5. Search in Google Scholar

Davie, C.A. (2008). A review of Parkinson’s disease. Br. Med. Bull. 86, 109–127. Search in Google Scholar

De Duve, C., and Beaufay, H. (1959). Tissue fractionation studies. 10. Influence of ischaemia on the state of some bound enzymes in rat liver. Biochem. J. 73, 610–616. Search in Google Scholar

De Duve, C., Pressman, B.C., Gianetto, R., Wattiaux, R., and Appelmans, F. (1955). Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 60, 604–617. Search in Google Scholar

Dehay, B., Bove, J., Rodriguez-Muela, N., Perier, C., Recasens, A., Boya, P., and Vila, M. (2010). Pathogenic lysosomal depletion in Parkinson’s disease. J. Neurosci. 30, 12535–12544. Search in Google Scholar

Eskelinen, E.L., Tanaka, Y., and Saftig, P. (2003). At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 13, 137–145. Search in Google Scholar

Fraldi, A., Klein, A. D., Medina, D.L., and Settembre, C. (2016). Brain disorders due to lysosomal dysfunction. Annu. Rev. Neurosci. 39, 277–295. Search in Google Scholar

George, J.M. (2002). The synucleins. Genome Biol. 3, REVIEWS3002. Search in Google Scholar

Giasson, B.I., Uryu, K., Trojanowski, J.Q., and Lee, V.M. (1999). Mutant and wild type human α-synucleins assemble into elongated filaments with distinct morphologies in vitro. J. Biol. Chem. 274, 7619–7622. Search in Google Scholar

Gieselmann, V. (1995). Lysosomal storage diseases. Biochim. Biophys. Acta 1270, 103–136. Search in Google Scholar

Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889. Search in Google Scholar

Infante, R.E., Radhakrishnan, A., Abi-Mosleh, L., Kinch, L.N., Wang, M.L., Grishin, N.V., Goldstein, J.L., and Brown, M.S. (2008). Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. J. Biol. Chem. 283, 1064–1075. Search in Google Scholar

Janvier, K., and Bonifacino, J.S. (2005). Role of the endocytic machinery in the sorting of lysosome-associated membrane proteins. Mol. Biol. Cell 16, 4231–4242. Search in Google Scholar

Kalia, L.V., and Lang, A.E. (2015). Parkinson’s disease. Lancet 386, 896–912. Search in Google Scholar

Klein, A. D., and Futerman, A.H. (2013). Lysosomal storage disorders: old diseases, present and future challenges. Pediatr. Endocrinol. Rev. 11 (Suppl. 1), 59–63. Search in Google Scholar

Klein, A. D., and Mazzulli, J.R. (2018). Is Parkinson’s disease a lysosomal disorder? Brain 141, 2255–2262. Search in Google Scholar

Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884. Search in Google Scholar

Kornfeld, S. (1992). Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Annu. Rev. Biochem. 61, 307–330. Search in Google Scholar

Lashuel, H.A., and Lansbury, P.T., Jr. (2006). Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q. Rev. Biophys. 39, 167–201. Search in Google Scholar

Lashuel, H.A., Petre, B.M., Wall, J., Simon, M., Nowak, R.J., Walz, T., and Lansbury, P.T., Jr. (2002). Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322, 1089–1102. Search in Google Scholar

Lesage, S., Anheim, M., Condroyer, C., Pollak, P., Durif, F., Dupuits, C., Viallet, F., Lohmann, et al. (2011). Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum. Mol. Genet. 20, 202–210. Search in Google Scholar

Mazzulli, J.R., Xu, Y.H., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G.A., Sidransky, E., Grabowski, G.A., et al. (2011). Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52. Search in Google Scholar

Mazzulli, J.R., Zunke, F., Tsunemi, T., Toker, N.J., Jeon, S., Burbulla, L.F., Patnaik, S., Sidransky, et al. (2016). Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson’s Patient Midbrain Neurons. J. Neurosci. 36, 7693–7706. Search in Google Scholar

McGlinchey, R.P., and Lee, J.C. (2015). Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. Proc. Natl. Acad. Sci. U.S. A. 112, 9322–9327. Search in Google Scholar

McNeill, A., Duran, R., Hughes, D.A., Mehta, A., and Schapira, A.H. (2012). A clinical and family history study of Parkinson’s disease in heterozygous glucocerebrosidase mutation carriers. J. Neurol. Neurosurg. Psychiatry 83, 853–854. Search in Google Scholar

Migdalska-Richards, A., Daly, L., Bezard, E., and Schapira, A.H. (2016). Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann. Neurol. 80, 766–775. Search in Google Scholar

Ohkuma, S., Moriyama, Y., and Takano, T. (1982). Identification and characterization of a proton pump on lysosomes by fluorescein-isothiocyanate-dextran fluorescence. Proc. Natl. Acad. Sci. USA 79, 2758–2762. Search in Google Scholar

Pastores, G.M. (1997). Gaucher’s Disease. Pathological features. Baillieres Clin. Haematol. 10, 739–749. Search in Google Scholar

Pitcairn, C., Wani, W.Y., and Mazzulli, J.R. (2019). Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson’s disease. Neurobiol. Dis. 122, 72–82. Search in Google Scholar

Platt, F.M., d’Azzo, A., Davidson, B.L., Neufeld, E.F., and Tifft, C.J. (2018). Lysosomal storage diseases. Nat. Rev. Dis. Primers 4, 27. Search in Google Scholar

Reczek, D., Schwake, M., Schroder, J., Hughes, H., Blanz, J., Jin, X., Brondyk, W., Van, P.S., et al. (2007). LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131, 770–783. Search in Google Scholar

Riederer, P., Berg, D., Casadei, N., Cheng, F., Classen, J., Dresel, C., Jost, W., Kruger, R., et al. (2019). α-Synuclein in Parkinson’s disease: causal or bystander? J. Neural Transm. (Vienna) 126, 815–840. Search in Google Scholar

Robak, L.A., Jansen, I. E., van Rooij, J., Uitterlinden, A.G., Kraaij, R., Jankovic, J., International Parkinson’s Disease Genomics Consortium, Heutink, P., et al. (2017). Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 140, 3191–3203. Search in Google Scholar

Sardi, S.P., Viel, C., Clarke, J., Treleaven, C.M., Richards, A.M., Park, H., Olszewski, M.A., Dodge, J.C., et al. (2017). Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc. Natl. Acad. Sci. U.S. A. 114, 2699–2704. Search in Google Scholar

Schulze, H., and Sandhoff, K. (2011). Lysosomal lipid storage diseases. Cold Spring Harb. Perspect. Biol. 3. Search in Google Scholar

Schwake, M., Schroder, B., and Saftig, P. (2013). Lysosomal membrane proteins and their central role in physiology. Traffic 14, 739–748. Search in Google Scholar

Settembre, C., Fraldi, A., Medina, D.L., and Ballabio, A. (2013). Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296. Search in Google Scholar

Shachar, T., Lo Bianco, C., Recchia, A., Wiessner, C., Raas-Rothschild, A., and Futerman, A.H. (2011). Lysosomal storage disorders and Parkinson’s disease: Gaucher disease and beyond. Mov. Disord. 26, 1593–1604. Search in Google Scholar

Sidransky, E., Nalls, M.A., Aasly, J.O., Aharon-Peretz, J., Annesi, G., Barbosa, E.R., Bar-Shira, A., Berg, D., et al. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 361, 1651–1661. Search in Google Scholar

Sulzer, D., and Edwards, R.H. (2019). The physiological role of α-synuclein and its relationship to Parkinson’s Disease. J. Neurochem. 150, 475–486. Search in Google Scholar

Suzuki, M., Fujikake, N., Takeuchi, T., Kohyama-Koganeya, A., Nakajima, K., Hirabayashi, Y., Wada, K., and Nagai, Y. (2015). Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson’s disease. Hum. Mol. Genet. 24, 6675–6686. Search in Google Scholar

Taguchi, Y.V., Liu, J., Ruan, J., Pacheco, J., Zhang, X., Abbasi, J., Keutzer, J., Mistry, P.K., et al. (2017). Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson’s disease. J. Neurosci. 37, 9617–9631. Search in Google Scholar

Xia, Q., Liao, L., Cheng, D., Duong, D.M., Gearing, M., Lah, J.J., Levey, A.I., and Peng, J. (2008). Proteomic identification of novel proteins associated with Lewy bodies. Front. Biosci. 13, 3850–3856. Search in Google Scholar

Zunke, F., Andresen, L., Wesseler, S., Groth, J., Arnold, P., Rothaug, M., Mazzulli, J.R., Krainc, D., et al. (2016). Characterization of the complex formed by beta-glucocerebrosidase and the lysosomal integral membrane protein type-2. Proc. Natl. Acad. Sci. USA 113, 3791–3796. Search in Google Scholar

Zunke, F., and Mazzulli, J.R. (2019). Modeling neuronopathic storage diseases with patient-derived culture systems. Neurobiol. Dis. 127, 147–162. Search in Google Scholar

Zunke, F., Moise, A.C., Belur, N.R., Gelyana, E., Stojkovska, I., Dzaferbegovic, H., Toker, N.J., Jeon, S., et al. (2018). Reversible conformational conversion of α-synuclein into toxic assemblies by glucosylceramide. Neuron 97, 92–107 e110. Search in Google Scholar

Published Online: 2020-01-09
Published in Print: 2020-02-25

© 2020 Walter de Gruyter GmbH, Berlin/Boston