Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Tai H-C, Schuman EM. 1.  2008. Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat. Rev. Neurosci. 9:11826–38 [Google Scholar]
  2. Mizushima N. 2.  2011. Autophagy in protein and organelle turnover. Cold Spring Harbor Symp. Quant. Biol. 76:397–402 [Google Scholar]
  3. Huotari J, Helenius A. 3.  2011. Endosome maturation. EMBO J 30:173481–500 [Google Scholar]
  4. de Duve C. 4.  2005. The lysosome turns fifty. Nat. Cell Biol. 7:9847–49 [Google Scholar]
  5. Sardiello M, Palmieri M, di Ronza A. 5.  et al. 2009. A gene network regulating lysosomal biogenesis and function. Science 325:5939473–77 [Google Scholar]
  6. Settembre C, Fraldi A, Medina DL. 6.  et al. 2013. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14:5283–96 [Google Scholar]
  7. Settembre C, Di Malta C, Polito VA. 7.  et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:60361429–33 [Google Scholar]
  8. He C, Klionsky DJ. 8.  2009. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43:67–93 [Google Scholar]
  9. Small SA, Petsko GA. 9.  2015. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat. Neurosci. 16:419–33 [Google Scholar]
  10. Hu Y-B, Dammer EB, Ren R-J. 10.  et al. 2015. The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration. Transl. Neurodegener. 4:18 [Google Scholar]
  11. Vilchez D, Saez I, Dillin A. 11.  2014. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5:5659 [Google Scholar]
  12. Webb JL, Ravikumar B, Atkins J. 12.  et al. 2003. Alpha-synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278:2725009–13 [Google Scholar]
  13. Cuervo AM, Stefanis L, Fredenburg R. 13.  et al. 2004. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:56881292–95 [Google Scholar]
  14. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z. 14.  et al. 2011. Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of alpha-synuclein. J. Neurosci. 31:4114508–20 [Google Scholar]
  15. Mak SK, McCormack AL, Manning-Bog AB. 15.  et al. 2010. Lysosomal degradation of alpha-synuclein in vivo. J. Biol. Chem. 285:1813621–29 [Google Scholar]
  16. Lashuel HA, Overk CR, Oueslati A. 16.  et al. 2013. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14:138–48 [Google Scholar]
  17. Lee MJ, Lee JH, Rubinsztein DC. 17.  2013. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog. Neurobiol. 105:49–59 [Google Scholar]
  18. Bruijn LI, Houseweart MK, Kato S. 18.  et al. 1998. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281:53841851–54 [Google Scholar]
  19. Kabuta T, Suzuki Y, Wada K. 19.  2006. Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J. Biol. Chem. 281:4130524–33 [Google Scholar]
  20. Platt FM, Walkey SU. 20.  2004. Lysosomal Disorders of the Brain Oxford, UK: Oxford Univ. Press
  21. Sidransky E, Nalls MA, Aasly JO. 21.  et al. 2009. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361:171651–61 [Google Scholar]
  22. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. 22.  2004. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351:191972–77 [Google Scholar]
  23. Goker-Alpan O, Giasson BI, Eblan MJ. 23.  et al. 2006. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67:5908–10 [Google Scholar]
  24. Gan-Or Z, Ozelius LJ, Bar-shira A. 24.  et al. 2013. The p.l302p mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 80:171606–10 [Google Scholar]
  25. Foo JN, Liany H, Bei JX. 25.  et al. 2013. A rare lysosomal enzyme gene SMPD1 variant (p.r591c) associates with Parkinson's disease. Neurobiol. Aging 34:122890.e13–2890.e15 [Google Scholar]
  26. Pastores GM, Hughes DA. 26.  1993. Gaucher disease. Genereviews RA Pagon, MP Adam, HH Ardinger 1,993–2,016 Seattle: Univ. Washington Press [Google Scholar]
  27. Neudorfer O, Giladi N, Elstein D. 27.  et al. 1996. Occurrence of Parkinson's syndrome in type 1 Gaucher disease. Q. J. Med. 89:9691–94 [Google Scholar]
  28. Bultron G, Kacena K, Pearson D. 28.  et al. 2010. The risk of Parkinson's disease in type 1 Gaucher disease. J. Inherit. Metab. Dis. 33:2167–73 [Google Scholar]
  29. Brockmann K, Srulijes K, Hauser AK. 29.  et al. 2011. GBA-associated PD presents with nonmotor characteristics. Neurology 77:3276–80 [Google Scholar]
  30. Alcalay RN, Caccappolo E, Mejia-Santana H. 30.  et al. 2012. Cognitive performance of GBA mutation carriers with early-onset PD: the core-PD study. Neurology 78:181434–40 [Google Scholar]
  31. Beavan M, Uk M, McNeill A. 31.  et al. 2015. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 72:2201–8 [Google Scholar]
  32. Parnetti L, Balducci C, Pierguidi L. 32.  et al. 2009. Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in dementia with Lewy bodies. Neurobiol. Dis. 34:3484–86 [Google Scholar]
  33. Alcalay RN, Levy OA, Waters CC. 33.  et al. 2015. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain 138:Pt. 92648–58 [Google Scholar]
  34. Pchelina SN, Nuzhnyi EP, Emelyanov AK. 34.  et al. 2014. Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases. Neurosci. Lett. 583:188–93 [Google Scholar]
  35. Mazzulli JR, Xu Y-H, Sun Y. 35.  et al. 2011. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:137–52 [Google Scholar]
  36. Schuchman EH, Desnick RJ. 36.  2001. Niemann Pick disease types A and B: acid sphingomyelinase deficiences. The Metabolic and Molecular Bases of Inherited Disease C Scriver, A Beaudet, W Sly 3,589–610 New York: McGraw Hill, 8th ed.. [Google Scholar]
  37. Spence M, Callahan J. 37.  1989. The Niemann Pick Group of Diseases New York: McGraw Hill
  38. McGovern MM, Wasserstein MP, Giugliani R. 38.  et al. 2008. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics 122:2e341–49 [Google Scholar]
  39. Gan-Or Z, Ozelius LJ, Bar-Shira A. 39.  et al. 2013. The p.l302p mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology 80:171606–10 [Google Scholar]
  40. Dagan E, Schlesinger I, Ayoub M. 40.  et al. 2015. Parkinsonism and related disorders: the contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews. Parkinsonism Relat. Disord. 21:91067–71 [Google Scholar]
  41. Deng S, Deng X, Song Z. 41.  et al. 2015. Systematic genetic analysis of the SMPD1 gene in Chinese patients with Parkinson's disease. Mol. Neurobiol. 5375025–29
  42. Delnooz CCS, Lefeber DJ, Langemeijer SMC. 42.  et al. 2010. New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. J. Neurol. Neurosurg. Psychiatry 81:9968–72 [Google Scholar]
  43. Keilani S, Lun Y, Stevens AC. 43.  et al. 2012. Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-beta peptide. J. Neurosci. 32:155223–36 [Google Scholar]
  44. Neufeld EF, Muenzer J. 44.  2001. The mucopolysaccharidoses. The Metabolic and Molecular Bases of Inherited Diseases CR Scriver, AL Beaudet, WS Sly 3421–52 New York: McGraw Hill, 8th ed.. [Google Scholar]
  45. Yogalingam G, Hopwood JJ. 45.  2001. Molecular genetics of mucopolysaccharidosis type Ia and IIb: diagnostic, clinical, and biological implications. Hum. Mutat. 18:4264–81 [Google Scholar]
  46. Hamano K, Hayashi M, Shioda K. 46.  et al. 2008. Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIb: analysis of human brain tissue. Acta Neuropathol 115:5547–59 [Google Scholar]
  47. Ginsberg SD, Galvin JE, Lee VM. 47.  et al. 1999. Accumulation of intracellular amyloid-beta peptide (abeta 1-40) in mucopolysaccharidosis brains. J. Neuropathol. Exp. Neurol. 58:8815–24 [Google Scholar]
  48. Ohmi K, Kudo LC, Ryazantsev S. 48.  et al. 2009. Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. PNAS 106:208332–37 [Google Scholar]
  49. Winder-Rhodes SE, Garcia-Reitbock P, Ban M. 49.  et al. 2012. Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome. Mov. Disord. 27:2312–15 [Google Scholar]
  50. Wang J, Lozier J, Johnson G. 50.  et al. 2008. Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nat. Biotechnol. 26:8901–8 [Google Scholar]
  51. Shayman JA. 51.  2010. Eliglustat tartrate: glucosylceramide synthase inhibitor treatment of type 1 Gaucher disease. Drugs Future 35:8613–20 [Google Scholar]
  52. Ridley CM, Thur KE, Shanahan J. 52.  et al. 2013. β-glucosidase 2 (GBA2) activity and imino sugar pharmacology. J. Biol. Chem. 288:3626052–66 [Google Scholar]
  53. Hammer MB, Eleuch-Fayache G, Schottlaender LV. 53.  et al. 2013. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am. J. Hum. Genet. 92:2245–51 [Google Scholar]
  54. Cox TM, Aerts JMFG, Andria G. 54.  et al. 2003. The role of the iminosugar n-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J. Inherit. Metab. Dis. 26:6513–26 [Google Scholar]
  55. Pastores GM, Elstein D, Hrebicek M. 55.  et al. 2007. Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies. Clin. Ther. 29:81645–54 [Google Scholar]
  56. Shayman JA, Larsen SD. 56.  2014. The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases. J. Lipid Res. 55:1–35 [Google Scholar]
  57. Kamath RS, Lukina E, Watman N. 57.  et al. 2014. Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. Skel. Rad. 43:101353–60 [Google Scholar]
  58. Shah AJ, Kapoor N, Crooks GM. 58.  et al. 2005. Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics 116:41022–25 [Google Scholar]
  59. Sands MS, Davidson BL. 59.  2006. Gene therapy for lysosomal storage diseases. Mol. Ther. 13:5839–49 [Google Scholar]
  60. Sundberg M, Isacson O. 60.  2014. Advances in stem-cell-generated transplantation therapy for Parkinson's disease. Expert Opin. Biol. Ther. 14:4437–53 [Google Scholar]
  61. Lieberman RL, Wustman BA, Huertas P. 61.  et al. 2007. Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat. Chem. Biol. 3:2101–7 [Google Scholar]
  62. Thaisrivongs S, Watenpaugh KD, Howe WJ. 62.  et al. 1995. Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors. J. Med. Chem. 38:183624–37 [Google Scholar]
  63. Mechtler TP, Stary S, Metz TF. 63.  et al. 2012. Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria. Lancet 379:9813335–41 [Google Scholar]
  64. Aflaki E, Stubblefield BK, Maniwang E. 64.  et al. 2014. Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs. Sci. Transl. Med. 6:240240ra73 [Google Scholar]
  65. Patnaik S, Zheng W, Choi JH. 65.  et al. 2012. Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. J. Med. Chem. 55:125734–48 [Google Scholar]
  66. Mazzulli JR, Zunke F, Tsunemi T. 66.  et al. 2016. Activation of β-glucocerebrosidase reduces pathological α-synuclein and restores lysosomal function in Parkinson's patient midbrain neurons. J. Neurosci. 36297693–706
  67. Wustman BA, Pine C, Ranes B. 67.  et al. 2008. Pharmacological chaperone therapy for Gaucher disease: mechanism of action, a survey of responsive mutations and phase I clinical trial results. Mol. Genet. Metab. 93:244 [Google Scholar]
  68. Boyd RE, Lee G, Rybczynski P. 68.  et al. 2013. Pharmacological chaperones as therapeutics for lysosomal storage diseases. J. Med. Chem. 56:72705–25 [Google Scholar]
  69. Narita A, Shirai K, Itamura S. 69.  et al. 2016. Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann. Clin. Transl. Neurol. 3:3200–15 [Google Scholar]
  70. Carstea ED, Morris JA, Coleman KG. 70.  et al. 1997. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:5323228–31 [Google Scholar]
  71. Kwon HJ, Abi-Mosleh L, Wang ML. 71.  et al. 2009. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137:71213–24 [Google Scholar]
  72. Brady RO, Filling-Katz MR, Barton NW. 72.  et al. 1989. Niemann-Pick disease types C and D. Neurol. Clin. 7:175–88 [Google Scholar]
  73. Auer IA, Schmidt ML, Lee VM. 73.  et al. 1995. Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease. Acta Neuropathol 90:6547–51 [Google Scholar]
  74. Hamilton RL. 74.  2000. Lewy bodies in Alzheimer's disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:3378–84 [Google Scholar]
  75. Saito Y, Suzuki K, Hulette CM. 75.  et al. 2004. Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J. Neuropathol. Exp. Neurol. 63:4323–28 [Google Scholar]
  76. Erickson RP, Larson-Thome K, Weberg L. 76.  et al. 2008. Variation in NPC1, the gene encoding Niemann-Pick C1, a protein involved in intracellular cholesterol transport, is associated with Alzheimer disease and/or aging in the Polish population. Neurosci. Lett. 447:2–3153–57 [Google Scholar]
  77. Lees AJ, Singleton AB. 77.  2007. Clinical heterogeneity of ATP13A2 linked disease (Kufor-Rakeb) justifies a Park designation. Neurology 68:191553–54 [Google Scholar]
  78. Ramirez A, Heimbach A, Grundemann J. 78.  et al. 2006. Hereditary Parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:101184–91 [Google Scholar]
  79. Bras J, Verloes A, Schneider SA. 79.  et al. 2012. Mutation of the Parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum. Mol. Genet. 21:122646–50 [Google Scholar]
  80. Williams DR, Hadeed A, al-Din ASN. 80.  et al. 2005. Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov. Disord. 20:101264–71 [Google Scholar]
  81. Schneider SA, Paisan-Ruiz C, Quinn NP. 81.  et al. 2010. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Mov. Disord. 25:897984 [Google Scholar]
  82. Mole SE, Williams RE, Goebel H-H. 82.  2011. The Neuronal Ceroid Lipofuscinoses (Batten Disease) Oxford, UK: Oxford Univ. Press, 2nd ed..
  83. Vilarino-Guell C, Soto AI, Lincoln SJ. 83.  et al. 2009. ATP13A2 variability in Parkinson disease. Hum. Mutat. 30:3406–10 [Google Scholar]
  84. Ramonet D, Podhajska A, Stafa K. 84.  et al. 2012. PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum. Mol. Genet. 21:81725–43 [Google Scholar]
  85. Kong SMY, Chan BKK, Park JS. 85.  et al. 2014. Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-synuclein externalization via exosomes. Hum. Mol. Genet. 23:112816–33 [Google Scholar]
  86. Tsunemi T, Krainc D. 86.  2014. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. 23112791–801
  87. Usenovic M, Tresse E, Mazzulli JR. 87.  et al. 2012. Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. J. Neurosci. 32:124240–46 [Google Scholar]
  88. Gitler AD, Chesi A, Geddie ML. 88.  et al. 2009. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41:3308–15 [Google Scholar]
  89. Dehay B, Martinez-Vicente M, Ramirez A. 89.  et al. 2012. Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove. Autophagy 8:91389–91 [Google Scholar]
  90. Jiang X, Sidhu R, Mydock-McGrane L. 90.  et al. 2016. Development of a bile acid–based newborn screen for Niemann-Pick disease type C. Sci. Transl. Med. 8:3371–11 [Google Scholar]
  91. Ohgane K, Karaki F, Dodo K. 91.  et al. 2013. Discovery of oxysterol-derived pharmacological chaperones for NPC1: implication for the existence of second sterol-binding site. Chem. Biol. 20:3391–402 [Google Scholar]
  92. Jiang X, Sidhu R, Porter FD. 92.  et al. 2011. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J. Lipid Res. 52:71435–45 [Google Scholar]
  93. Ren HY, Grove DE, La Rosa OD. 93.  et al. 2013. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol. Biol. Cell 24:193016–24 [Google Scholar]
  94. Schilsky RL. 94.  2014. Implementing personalized cancer care. Nat. Rev. Clin. Oncol. 11:7432–38 [Google Scholar]
  95. Gotovac K, Hajnšek S, Pašić MB. 95.  et al. 2013. Personalized medicine in neurodegenerative diseases: how far away?. Mol. Diagn. Ther. 18:117–24 [Google Scholar]
  96. Kumar KR, Ramirez A, Gobel A. 96.  et al. 2013. Glucocerebrosidase mutations in a Serbian Parkinson's disease population. Eur. J. Neurol. 20:2402–5 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error