Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Are Lysosomes Potential Therapeutic Targets for Parkinson’s Disease?

Author(s): Alessandro Petese, Valentina Cesaroni, Silvia Cerri and Fabio Blandini*

Volume 21, Issue 8, 2022

Published on: 26 November, 2021

Page: [642 - 655] Pages: 14

DOI: 10.2174/1871527320666210809123630

Price: $65

Abstract

Parkinson´s Disease (PD) is the second most common neurodegenerative disorder, affecting ~2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy Bodies (LBs). Recently, Genome-Wide Association Studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

Keywords: Parkinson´s disease, PD GWAS loci, lysosomal pathways, alpha-synuclein, therapeutic approaches, LBs.

« Previous Next »
Graphical Abstract

[1]
Kalia LV, Lang AE, Shulman G. Parkinson’s disease. Lancet 2015; 386(9996): 896-912.
[http://dx.doi.org/10.1016/S0140-6736(14)61393-3] [PMID: 25904081]
[2]
Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med 2020; 36(1): 1-12.
[http://dx.doi.org/10.1016/j.cger.2019.08.002] [PMID: 31733690]
[3]
Meade RM, Fairlie DP, Mason JM. Alpha-synuclein structure and Parkinson’ s disease – lessons and emerging principles. 2019; 1: 1-14.
[4]
Wildburger NC, Hartke A-S, Schidlitzki A, Richter F. Current evidence for a bidirectional loop between the lysosome and alpha-synuclein proteoforms. Front Cell Dev Biol 2020; 8: 598446.
[http://dx.doi.org/10.3389/fcell.2020.598446] [PMID: 33282874]
[5]
Roeters SJ, Iyer A, Pletikapić G, Kogan V, Subramaniam V, Woutersen S. Evidence for intramolecular antiparallel beta-sheet structure in alpha-synuclein fibrils from a combination of two-dimensional infrared spectroscopy and atomic force microscopy. Nat Publ Gr 2017; 2: 1-11.
[http://dx.doi.org/10.1038/srep41051]
[6]
Burré J, Sharma M, Südhof TC. Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci 2015; 35(13): 5221-32.
[http://dx.doi.org/10.1523/JNEUROSCI.4650-14.2015] [PMID: 25834048]
[7]
Galvagnion C, Buell AK, Meisl G, et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol 2015; 11(3): 229-34.
[http://dx.doi.org/10.1038/nchembio.1750] [PMID: 25643172]
[8]
Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003; 37(4): 583-95.
[http://dx.doi.org/10.1016/S0896-6273(03)00024-2] [PMID: 12597857]
[9]
Klein C, Westenberger A. Genetics of Parkinson’s disease. Oxidative Stress Neurodegener Disord 2007; 663-97.
[http://dx.doi.org/10.1016/B978-044452809-4/50169-1]
[10]
Chang D, Nalls MA, Hallgrímsdóttir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 2017; 49(10): 1511-6.
[http://dx.doi.org/10.1038/ng.3955] [PMID: 28892059]
[11]
Smolders S, Van Broeckhoven C. Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis. Acta Neuropathol Commun 2020; 8(1): 63.
[http://dx.doi.org/10.1186/s40478-020-00935-4] [PMID: 32375870]
[12]
Blauwendraat C, Reed X, Krohn L, et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain 2020; 143(1): 234-48.
[http://dx.doi.org/10.1093/brain/awz350] [PMID: 31755958]
[13]
Robak LA, Jansen IE, van Rooij J, et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 2017; 140(12): 3191-203.
[http://dx.doi.org/10.1093/brain/awx285] [PMID: 29140481]
[14]
Klein AD, Mazzulli JR. Is Parkinson’s disease a lysosomal disorder? Brain 2018; 141(8): 2255-62.
[http://dx.doi.org/10.1093/brain/awy147] [PMID: 29860491]
[15]
Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 2014; 46(9): 989-93.
[http://dx.doi.org/10.1038/ng.3043] [PMID: 25064009]
[16]
Cuervo AM, Stafanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 2004; 305: 1292-5.
[http://dx.doi.org/10.1126/science.1101738]
[17]
Wong E, Cuervo AM. Integration of clearance mechanisms: The proteasome and autophagy. Cold Spring Harb Perspect Biol 2010; 2(12): a006734.
[http://dx.doi.org/10.1101/cshperspect.a006734] [PMID: 21068151]
[18]
Navarro-Romero A, Montpeyó M, Martinez-Vicente M. The emerging role of the lysosome in parkinson’s disease. Cells 2020; 9(11): 1-25.
[http://dx.doi.org/10.3390/cells9112399] [PMID: 33147750]
[19]
Boya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene 2008; 27(50): 6434-51.
[http://dx.doi.org/10.1038/onc.2008.310] [PMID: 18955971]
[20]
Luzio JP, Hackmann Y, Dieckmann NMG, Griffiths GM. The biogenesis of lysosomes and lysosome-related organelles. Cold Spring Harb Perspect Biol 2014; 6(9): a016840.
[http://dx.doi.org/10.1101/cshperspect.a016840] [PMID: 25183830]
[21]
Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S. TFEB links autophagy to lysosomal biogenesis. Science 2011; 332: 1429-33.
[http://dx.doi.org/10.1126/science.1204592]
[22]
Ni X, Canuel M, Morales CR. The sorting and trafficking of lysosomal proteins. J. 2006; 22: 899-913.
[23]
Griffiths G, Hoflack B, Simons K, Mellman I, Kornfeld S. The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 1988; 52(3): 329-41.
[http://dx.doi.org/10.1016/S0092-8674(88)80026-6] [PMID: 2964276]
[24]
Xu J, Xilouri M, Bruban J, et al. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 2011; 32(12): 2326.e5-2326.e16.
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.06.017] [PMID: 21820214]
[25]
Zhou X, Paushter DH, Feng T, Sun L, Reinheckel T, Hu F. Lysosomal processing of progranulin. Mol Neurodegener 2017; 12(1): 62.
[http://dx.doi.org/10.1186/s13024-017-0205-9] [PMID: 28835281]
[26]
Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov 2019; 18(12): 923-48.
[http://dx.doi.org/10.1038/s41573-019-0036-1] [PMID: 31477883]
[27]
Cuervo AM. Chaperone-mediated autophagy: Selectivity pays off. Cell 2009; 2(2): 2.
[http://dx.doi.org/10.1016/j.tem.2009.10.003] [PMID: 19857975]
[28]
Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 2008; 283(35): 23542-56.
[http://dx.doi.org/10.1074/jbc.M801992200] [PMID: 18566453]
[29]
Senkevich K, Gan-Or Z. Autophagy lysosomal pathway dysfunction in Parkinson’s disease; evidence from human genetics. Parkinsonism Relat Disord 2020; 73: 60-71.
[http://dx.doi.org/10.1016/j.parkreldis.2019.11.015] [PMID: 31761667]
[30]
Ciechanover A, Kwon YT. Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies. Exp Mol Med 2015; 47: e147.
[http://dx.doi.org/10.1038/emm.2014.117] [PMID: 25766616]
[31]
Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 2009; 4(5): e5515.
[http://dx.doi.org/10.1371/journal.pone.0005515] [PMID: 19436756]
[32]
Murphy KE, Gysbers AM, Abbott SK, et al. Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson’s disease. Mov Disord 2015; 30(12): 1639-47.
[http://dx.doi.org/10.1002/mds.26141] [PMID: 25594542]
[33]
Alvarez-Erviti L PhD, Maria C, Rodriguez-Oroz MS PhD, et al. Chaperone- mediated autophagy markers in parkinson disease brains. Arch Neurol 2015; 67: 1464-72.
[http://dx.doi.org/10.1001/archneurol.2010.198]
[34]
Buratta S, Tancini B, Sagini K, et al. Lysosomal exocytosis, exosome release and secretory autophagy: The autophagic- and endo-lysosomal systems go extracellular. Int J Mol Sci 2020; 21(7): E2576.
[http://dx.doi.org/10.3390/ijms21072576] [PMID: 32276321]
[35]
Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function. Nat Rev Mol Cell Biol 2009; 10(9): 623-35.
[http://dx.doi.org/10.1038/nrm2745] [PMID: 19672277]
[36]
Emmanouilidou E, Vekrellis K. Exocytosis and spreading of normal and aberrant a -synuclein. Brain Pathol. 2016; 26: 398-403.
[http://dx.doi.org/10.1111/bpa.12373]
[37]
Mindell JA. Lysosomal acidification mechanisms. Annu Rev Physiol 2012; 74: 69-86.
[http://dx.doi.org/10.1146/annurev-physiol-012110-142317] [PMID: 22335796]
[38]
Cuervo AM, Dice JF. Age-related decline in chaperone-mediated autophagy. J Biol Chem 2000; 275(40): 31505-13.
[http://dx.doi.org/10.1074/jbc.M002102200] [PMID: 10806201]
[39]
Manzoni C, Mamais A, Roosen DA, et al. mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1. Sci Rep 2016; 6: 35106.
[http://dx.doi.org/10.1038/srep35106] [PMID: 27731364]
[40]
Wallings R, Connor-Robson N, Wade-Martins R. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Hum Mol Genet 2019; 28(16): 2696-710.
[http://dx.doi.org/10.1093/hmg/ddz088] [PMID: 31039583]
[41]
Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and α-synuclein. J Neurosci 2014; 34(46): 15281-7.
[http://dx.doi.org/10.1523/JNEUROSCI.1629-14.2014] [PMID: 25392495]
[42]
Ramirez A, Heimbach A, Gründemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38(10): 1184-91.
[http://dx.doi.org/10.1038/ng1884] [PMID: 16964263]
[43]
Kong SMY, Chan BKK, Park JS, et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes. Hum Mol Genet 2014; 23(11): 2816-33.
[http://dx.doi.org/10.1093/hmg/ddu099] [PMID: 24603074]
[44]
Daniel G, Musso A, Tsika E, et al. α-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson’s disease occurs independent of ATP13A2 (PARK9). Neurobiol Dis 2015; 73: 229-43.
[http://dx.doi.org/10.1016/j.nbd.2014.10.007] [PMID: 25461191]
[45]
Kett LR, Stiller B, Bernath MM, et al. α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2. J Neurosci 2015; 35(14): 5724-42.
[http://dx.doi.org/10.1523/JNEUROSCI.0632-14.2015] [PMID: 25855184]
[46]
Schultheis PJ, Fleming SM, Clippinger AK, et al. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet 2013; 22(10): 2067-82.
[http://dx.doi.org/10.1093/hmg/ddt057] [PMID: 23393156]
[47]
Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. TMEM175 is an organelle k(+) channel regulating lysosomal function. Cell 2015; 162(5): 1101-12.
[http://dx.doi.org/10.1016/j.cell.2015.08.002] [PMID: 26317472]
[48]
Jinn S, Drolet RE, Cramer PE, et al. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc Natl Acad Sci USA 2017; 114(9): 2389-94.
[http://dx.doi.org/10.1073/pnas.1616332114] [PMID: 28193887]
[49]
Krohn L, Öztürk TN, Vanderperre B, et al. Genetic, structural, and functional evidence link tmem175 to synucleinopathies. Ann Neurol 2020; 87(1): 139-53.
[http://dx.doi.org/10.1002/ana.25629] [PMID: 31658403]
[50]
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011; 146(1): 37-52.
[http://dx.doi.org/10.1016/j.cell.2011.06.001] [PMID: 21700325]
[51]
Butters TD. Gaucher disease. Curr Opin Chem Biol 2007; 11(4): 412-8.
[http://dx.doi.org/10.1016/j.cbpa.2007.05.035] [PMID: 17644022]
[52]
Malini E, Zampieri S, Deganuto M, et al. Role of LIMP-2 in the intracellular trafficking of β-glucosidase in different human cellular models. FASEB J 2015; 29(9): 3839-52.
[http://dx.doi.org/10.1096/fj.15-271148] [PMID: 26018676]
[53]
Romero R, Ramanathan A, Yuen T, et al. Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning. Proc Natl Acad Sci USA 2019; 116(11): 5086-95.
[http://dx.doi.org/10.1073/pnas.1818411116] [PMID: 30808805]
[54]
Beutler E. Gaucher disease: New molecular approaches to diagnosis and treatment. Science 1992; 256: 794-9.
[http://dx.doi.org/10.1126/science.1589760]
[55]
Blauwendraat C, Bras JM, Nalls MA, Lewis PA, Hernandez DG, Singleton AB. Coding variation in GBA explains the majority of the SYT11-GBA Parkinson’s disease GWAS locus. Mov Disord 2018; 33(11): 1821-3.
[http://dx.doi.org/10.1002/mds.103] [PMID: 30302829]
[56]
Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 2009; 132(Pt 7): 1783-94.
[http://dx.doi.org/10.1093/brain/awp044] [PMID: 19286695]
[57]
Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014; 137(Pt 5): 1304-22.
[http://dx.doi.org/10.1093/brain/awu002] [PMID: 24531622]
[58]
Gegg ME, Burke D, Heales SJR, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 2012; 72(3): 455-63.
[http://dx.doi.org/10.1002/ana.23614] [PMID: 23034917]
[59]
Rocha EM, Smith GA, Park E, et al. Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann Clin Transl Neurol 2015; 2(4): 433-8.
[http://dx.doi.org/10.1002/acn3.177] [PMID: 25909088]
[60]
Murphy KE, Gysbers AM, Abbott SK, et al. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease. Brain 2014; 137(Pt 3): 834-48.
[http://dx.doi.org/10.1093/brain/awt367] [PMID: 24477431]
[61]
Sardi SP, Clarke J, Kinnecom C, et al. CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc Natl Acad Sci USA 2011; 108(29): 12101-6.
[http://dx.doi.org/10.1073/pnas.1108197108] [PMID: 21730160]
[62]
Taguchi YV, Liu J, Ruan J, et al. Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated parkinson’s disease. J Neurosci 2017; 37(40): 9617-31.
[http://dx.doi.org/10.1523/JNEUROSCI.1525-17.2017] [PMID: 28847804]
[63]
Zunke F, Moise AC, Belur NR, et al. Reversible conformational conversion of α-synuclein into toxic assemblies by glucosylceramide. Neuron 2018; 97(1): 92-107.e10.
[http://dx.doi.org/10.1016/j.neuron.2017.12.012] [PMID: 29290548]
[64]
Manning-Boğ AB, Schüle B, Langston JW. Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism. Neurotoxicology 2009; 30(6): 1127-32.
[http://dx.doi.org/10.1016/j.neuro.2009.06.009] [PMID: 19576930]
[65]
Rocha EM, Smith GA, Park E, et al. Sustained systemic glucocerebrosidase inhibition induces brain α-synuclein aggregation, microglia and complement c1q activation in mice. Antioxid Redox Signal 2015; 23(6): 550-64.
[http://dx.doi.org/10.1089/ars.2015.6307] [PMID: 26094487]
[66]
Mus L, Siani F, Giuliano C, Ghezzi C, Cerri S, Blandini F. Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity. Neurobiol Dis 2019; 124: 289-96.
[http://dx.doi.org/10.1016/j.nbd.2018.12.001] [PMID: 30521842]
[67]
Henderson MX, Sedor S, McGeary I, et al. Glucocerebrosidase activity modulates neuronal susceptibility to pathological α-synuclein insult. Neuron 2020; 105(5): 822-836.e7.
[http://dx.doi.org/10.1016/j.neuron.2019.12.004] [PMID: 31899072]
[68]
Eitan E, Suire C, Zhang S, Mattson MP. Impact of lysosome status on extracellular vesicle content and release. Ageing Res Rev 2016; 32: 65-74.
[http://dx.doi.org/10.1016/j.arr.2016.05.001] [PMID: 27238186]
[69]
Gruschus JM, Jiang Z, Yap TL, et al. Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C. Biochem Biophys Res Commun 2015; 457(4): 561-6.
[http://dx.doi.org/10.1016/j.bbrc.2015.01.024] [PMID: 25600808]
[70]
Ouled Amar Bencheikh B, Leveille E, Ruskey JA, et al. Sequencing of the GBA coactivator, Saposin C, in Parkinson disease. Neurobiol Aging 2018; 72: 187.e1-3.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.034] [PMID: 30037697]
[71]
Chen YP, Gu XJ, Ou RW, Zhang LY, Hou YB, Liu KC. Genetic analysis of prosaposin, the lysosomal storage disorder gene in parkinson’s disease. Mol Neurobiol 2020.
[http://dx.doi.org/10.1007/s12035-020-02218-4] [PMID: 33219486]
[72]
Oji Y, Hatano T, Ueno SI, et al. Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease. Brain 2020; 143(4): 1190-205.
[http://dx.doi.org/10.1093/brain/awaa064] [PMID: 32201884]
[73]
Ysselstein D, Shulman JM, Krainc D. Emerging links between pediatric lysosomal storage diseases and adult parkinsonism. Mov Disord 2019; 34(5): 614-24.
[http://dx.doi.org/10.1002/mds.27631] [PMID: 30726573]
[74]
Harzer K, Knoblich R, Rolfs A, Bauer P, Eggers J. Residual galactosylsphingosine (psychosine) β-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 2002; 317(1-2): 77-84.
[http://dx.doi.org/10.1016/S0009-8981(01)00791-4] [PMID: 11814461]
[75]
Smith BR, Santos MB, Marshall MS, Cantuti L, Lopez-rosas A, Li G. Pathogenesis of Krabbe disease. J Pathol. 2015; 232: 509-21.
[http://dx.doi.org/10.1002/path.4328]
[76]
Marshall MS, Bongarzone ER. Beyond Krabbe’s disease: The potential contribution of galactosylceramidase deficiency to neuronal vulnerability in late-onset synucleinopathies. J Neurosci Res 2016; 94(11): 1328-32.
[http://dx.doi.org/10.1002/jnr.23751] [PMID: 27638614]
[77]
Marshall MS, Jakubauskas B, Bogue W, et al. Analysis of age-related changes in psychosine metabolism in the human brain. PLoS One 2018; 13(2): e0193438.
[http://dx.doi.org/10.1371/journal.pone.0193438] [PMID: 29481565]
[78]
Hook V, Yoon M, Mosier C, et al. Cathepsin B in neurodegeneration of Alzheimer’s disease, traumatic brain injury, and related brain disorders. Biochim Biophys Acta Proteins Proteomics 2020; 1868(8): 140428.
[http://dx.doi.org/10.1016/j.bbapap.2020.140428] [PMID: 32305689]
[79]
Sloane BF, Yan S, Podgorski I, et al. Cathepsin B and tumor proteolysis: Contribution of the tumor microenvironment. Semin Cancer Biol 2005; 15(2): 149-57.
[http://dx.doi.org/10.1016/j.semcancer.2004.08.001] [PMID: 15652460]
[80]
Tsujimura A, Taguchi K, Watanabe Y, et al. Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous α-synuclein fibrils. Neurobiol Dis 2015; 73: 244-53.
[http://dx.doi.org/10.1016/j.nbd.2014.10.011] [PMID: 25466281]
[81]
McGlinchey RP, Lee JC. Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. Proc Natl Acad Sci USA 2015; 112(30): 9322-7.
[http://dx.doi.org/10.1073/pnas.1500937112] [PMID: 26170293]
[82]
McGlinchey RP, Lacy SM, Huffer KE, Tayebi N, Sidransky E, Lee JC. C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson’s disease. J Biol Chem 2019; 294(25): 9973-84.
[http://dx.doi.org/10.1074/jbc.RA119.008930] [PMID: 31092553]
[83]
Murray IVJ, Giasson BI, Quinn SM, et al. Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 2003; 42(28): 8530-40.
[http://dx.doi.org/10.1021/bi027363r] [PMID: 12859200]
[84]
van der Wateren IM, Knowles TPJ, Buell AK. C-terminal truncation of a-synuclein promotes amyloid fibril amplification at physiological pH. Chem Sci (Camb) 2018; 9
[http://dx.doi.org/10.1039/C8SC01109E] [PMID: 30061982]
[85]
Hoyer W, Cherny D, Subramaniam V, Jovin TM. Impact of the acidic C-terminal region comprising amino acids 109-140 on alpha-synuclein aggregation in vitro. Biochemistry 2004; 43(51): 16233-42.
[http://dx.doi.org/10.1021/bi048453u] [PMID: 15610017]
[86]
Ding Q, Zhu H. Upregulation of PSMB8 and cathepsins in the human brains of dementia with Lewy bodies. Neurosci Lett 2018; 678: 131-7.
[http://dx.doi.org/10.1016/j.neulet.2018.05.022] [PMID: 29775672]
[87]
Erickson AH, Blobel G. Carboxyl-terminal proteolytic processing during biosynthesis of the lysosomal enzymes β-glucuronidase and cathepsin D. Biochemistry 1983; 22(22): 5201-5.
[http://dx.doi.org/10.1021/bi00291a021] [PMID: 6360205]
[88]
Conner GE. The role of the cathepsin D propeptide in sorting to the lysosome. J Biol Chem 1992; 267(30): 21738-45.
[http://dx.doi.org/10.1016/S0021-9258(19)36674-8] [PMID: 1400484]
[89]
Vidoni. the role of cathepsin D in the pathogenensis of human neurodegnerative disease. Harv Bus Rev 2008; 86: 84-92.
[http://dx.doi.org/10.1002/med]
[90]
Sevlever D, Jiang P, Yen SHC. Cathepsin D is the main lysosomal enzyme involved in the degradation of α-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 2008; 47(36): 9678-87.
[http://dx.doi.org/10.1021/bi800699v] [PMID: 18702517]
[91]
Qiao L, Hamamichi S, Caldwell KA, et al. Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 2008; 1: 17.
[http://dx.doi.org/10.1186/1756-6606-1-17] [PMID: 19021916]
[92]
Tayebi N, Lopez G, Do J, Sidransky E. Pro-cathepsin D, prosaposin, and progranulin: Lysosomal networks in parkinsonism. Trends Mol Med 2020; 26(10): 913-23.
[http://dx.doi.org/10.1016/j.molmed.2020.07.004] [PMID: 32948448]
[93]
Hiraiwa M, Martin BM, Kishimoto Y, Conner GE, Tsuji S, O’Brien JS. Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): Its mechanism and inhibition by ganglioside. Arch Biochem Biophys 1997; 341(1): 17-24.
[http://dx.doi.org/10.1006/abbi.1997.9958] [PMID: 9143348]
[94]
Yang SY, Gegg M, Chau D, Schapira A. Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation. Neurobiol Dis 2020; 134: 104620.
[http://dx.doi.org/10.1016/j.nbd.2019.104620] [PMID: 31634558]
[95]
Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci USA 2013; 110(19): E1817-26.
[http://dx.doi.org/10.1073/pnas.1305623110] [PMID: 23610405]
[96]
Kilpatrick K, Zeng Y, Hancock T, Segatori L. Genetic and chemical activation of TFEB mediates clearance of aggregated α - synuclein. 2015; 1-21.
[http://dx.doi.org/10.1371/journal.pone.0120819]
[97]
Xilouri M, Brekk OR, Landeck N, Pitychoutis PM, Papasilekas T, Papadopoulou-daifoti Z. Boosting chaperone-mediated autophagy in vivo mitigates a -synuclein-induced neurodegeneration. 2013; 2130-46.
[http://dx.doi.org/10.1093/brain/awt131]
[98]
Wu JZ, Ardah M, Haikal C, et al. Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy. Transl Neurodegener 2019; 8: 18.
[http://dx.doi.org/10.1186/s40035-019-0159-7] [PMID: 31223479]
[99]
Tsunemi T, Perez-Rosello T, Ishiguro Y, et al. Increased lysosomal exocytosis induced by lysosomal Ca2+ channel agonists protects human dopaminergic neurons from α-synuclein toxicity. J Neurosci 2019; 39(29): 5760-72.
[http://dx.doi.org/10.1523/JNEUROSCI.3085-18.2019] [PMID: 31097622]
[100]
Fine M, Schmiege P, Li X. Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nat Commun 2018; 9(1): 4192.
[http://dx.doi.org/10.1038/s41467-018-06493-7] [PMID: 30305615]
[101]
Hui L, Soliman ML, Geiger NH, Miller NM, Afghah Z, Lakpa KL. Acidifying endolysosomes prevented low-density lipoprotein-induced amyloidogenesis. J Alzheimers Dis 2018.
[http://dx.doi.org/10.3233/JAD-180941] [PMID: 30594929]
[102]
Bourdenx M, Daniel J, Genin E, et al. Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases. Autophagy 2016; 12(3): 472-83.
[http://dx.doi.org/10.1080/15548627.2015.1136769] [PMID: 26761717]
[103]
Prévot G, Soria FN, Thiolat ML, et al. Harnessing lysosomal ph through plga nanoemulsion as a treatment of lysosomal-related neurodegenerative diseases. Bioconjug Chem 2018; 29(12): 4083-9.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00697] [PMID: 30424597]
[104]
Lee C, Guo J, Zeng W, et al. The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature 2017; 547(7664): 472-5.
[http://dx.doi.org/10.1038/nature23269] [PMID: 28723891]
[105]
Marques ARA, Di Spiezio A, Thießen N, Schmidt L, Grötzinger J, Lüllmann-rauch R. Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis. Autophagy 2019; 0: 1-15.
[http://dx.doi.org/10.1080/15548627.2019.1637200] [PMID: 31282275]
[106]
Ambrosi G, Ghezzi C, Zangaglia R, Levandis G, Pacchetti C, Blandini F. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson’s disease cells. Neurobiol Dis 2015; 82: 235-42.
[http://dx.doi.org/10.1016/j.nbd.2015.06.008] [PMID: 26094596]
[107]
Kopytova AE, Rychkov GN, Nikolaev MA, et al. Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism. Parkinsonism Relat Disord 2021; 84: 112-21.
[http://dx.doi.org/10.1016/j.parkreldis.2021.02.003] [PMID: 33609962]
[108]
McNeill A, Magalhaes J, Shen C, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain 2014; 137(Pt 5): 1481-95.
[http://dx.doi.org/10.1093/brain/awu020] [PMID: 24574503]
[109]
Aflaki E, Borger DK, Moaven N, et al. A new glucocerebrosidase chaperone reduces α-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism. J Neurosci 2016; 36(28): 7441-52.
[http://dx.doi.org/10.1523/JNEUROSCI.0636-16.2016] [PMID: 27413154]
[110]
Aflaki E, Moaven N, Borger DK, et al. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell 2016; 15(1): 77-88.
[http://dx.doi.org/10.1111/acel.12409] [PMID: 26486234]
[111]
Sanchez-Martinez A, Beavan M, Gegg ME, Chau KY, Whitworth AJ, Schapira AHV. Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep 2016; 6: 31380.
[http://dx.doi.org/10.1038/srep31380] [PMID: 27539639]
[112]
den Heijer JM, Kruithof AC, van Amerongen G, et al. A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. Br J Clin Pharmacol 2021; 1-13.
[http://dx.doi.org/10.1111/bcp.14772] [PMID: 33576113]
[113]
Benz J, Rufer AC, Huber S, et al. Novel β-glucocerebrosidase activators that bind to a new pocket at a dimer interface and induce dimerization. Angew Chem Int Ed Engl 2021; 60(10): 5436-42.
[http://dx.doi.org/10.1002/anie.202013890] [PMID: 33238058]
[114]
Sardi SP, Viel C, Clarke J, et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc Natl Acad Sci USA 2017; 114(10): 2699-704.
[http://dx.doi.org/10.1073/pnas.1616152114] [PMID: 28223512]
[115]
Mullin S, Smith L, Lee K, et al. Ambroxol for the treatment of patients with parkinson disease with and without glucocerebrosidase gene mutations: A nonrandomized, noncontrolled trial. JAMA Neurol 2020; 77(4): 427-34.
[http://dx.doi.org/10.1001/jamaneurol.2019.4611] [PMID: 31930374]
[116]
Silveira CRA, MacKinley J, Coleman K, et al. Ambroxol as a novel disease-modifying treatment for Parkinson’s disease dementia: Protocol for a single-centre, randomized, double-blind, placebo- controlled trial. BMC Neurol 2019; 19(1): 20.
[http://dx.doi.org/10.1186/s12883-019-1252-3] [PMID: 30738426]
[117]
Istaiti M, Revel-Vilk S, Becker-Cohen M, et al. Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data. Am J Hematol 2021; 96(5): 545-51.
[http://dx.doi.org/10.1002/ajh.26131] [PMID: 33606887]
[118]
Parenti G, Andria G, Valenzano KJ. Pharmacological chaperone therapy: Preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders. Mol Ther 2015; 23(7): 1138-48.
[http://dx.doi.org/10.1038/mt.2015.62] [PMID: 25881001]
[119]
Peterschmitt MJ, Crawford NPS, Gaemers SJM, Ji AJ, Sharma J, Pham TT. Pharmacokinetics, pharmacodynamics, safety, and tolerability of oral venglustat in healthy volunteers. Clin Pharmacol Drug Dev 2020; 02142
[http://dx.doi.org/10.1002/cpdd.865] [PMID: 32851809]
[120]
Judith Peterschmitt M. Safety, pharmacokinetics, and pharmacodynamics of oral venglustat in the japanese and the rest of the world Parkinson’s disease population with a GBA mutation: Results from part 1 of the MOVES-PD study (809). Neurology 2020; 9410.1002/cpdd.865.
[121]
Fernandes HJR, Patikas N, Foskolou S, et al. Single-cell transcriptomics of Parkinson’s disease human in vitro models reveals dopamine neuron-specific stress responses. Cell Rep 2020; 33(2): 108263.
[http://dx.doi.org/10.1016/j.celrep.2020.108263] [PMID: 33053338]

Rights & Permissions Print Cite
Article Metrics
50
1
© 2024 Bentham Science Publishers | Privacy Policy