Recent studies of autophagic and lysosomal pathways have significantly changed our understanding of lysosomes; once thought to be simple degradative and recycling centers, lysosomes are now known to be organelles capable of influencing signal transduction, via the mammalian target of rapamycin complex 1 (mTORC1), and regulating gene expression, via transcription factor EB (TFEB) and other transcription factors. These pathways are particularly relevant to maintaining brain homeostasis, as dysfunction of the endolysosomal and autophagic pathways has been associated with common neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, and lysosomal storage disorders, a group of inherited disorders characterized by the intralysosomal buildup of partially degraded metabolites. This review focuses on the cellular biology of lysosomes and discusses the possible mechanisms by which disruption of their function contributes to neurodegeneration. We also review and discuss how targeting TFEB and lysosomes may offer innovative therapeutic approaches for treating a wide range of neurological conditions.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Arias E, Koga H, Diaz A, Mocholi E, Patel B, Cuervo AM. 2015. Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy. Mol. Cell 59:270–84 [Google Scholar]
  2. Bar-On P, Rockenstein E, Adame A, Ho G, Hashimoto M, Masliah E. 2006. Effects of the cholesterol-lowering compound methyl-β-cyclodextrin in models of α-synucleinopathy. J. Neurochem. 98:1032–45 [Google Scholar]
  3. BasuRay S, Mukherjee S, Romero EG, Seaman MN, Wandinger-Ness A. 2013. Rab7 mutants associated with Charcot-Marie-Tooth disease cause delayed growth factor receptor transport and altered endosomal and nuclear signaling. J. Biol. Chem. 288:1135–49 [Google Scholar]
  4. Bellettato CM, Scarpa M. 2010. Pathophysiology of neuropathic lysosomal storage disorders. J. Inherit. Metab. Dis. 33:347–62 [Google Scholar]
  5. Bertram L, Tanzi RE. 2005. The genetic epidemiology of neurodegenerative disease. J. Clin. Investig. 115:1449–57 [Google Scholar]
  6. Boustany RM. 2013. Lysosomal storage diseases—the horizon expands. Nat. Rev. Neurol. 9:583–98 [Google Scholar]
  7. Bras J, Guerreiro R, Hardy J. 2015. SnapShot: genetics of Parkinson's disease. Cell 160:570–70 [Google Scholar]
  8. Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ. 2012. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum. Mol. Genet. 21:2646–50 [Google Scholar]
  9. Burgoyne RD, Morgan A. 2011. Chaperoning the SNAREs: a role in preventing neurodegeneration?. Nat. Cell Biol. 13:8–9 [Google Scholar]
  10. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. 2010. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–67 [Google Scholar]
  11. Butler JD, Vanier MT, Pentchev PG. 1993. Niemann-Pick C disease: Cystine and lipids accumulate in the murine model of this lysosomal cholesterol lipidosis. Biochem. Biophys. Res. Commun. 196:154–59 [Google Scholar]
  12. Cang C, Aranda K, Seo YJ, Gasnier B, Ren D. 2015. TMEM175 is an organelle K+ channel regulating lysosomal function. Cell 162:1101–12 [Google Scholar]
  13. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K. et al. 2013. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152:778–90 [Google Scholar]
  14. Cao Q, Zhong XZ, Zou Y, Murrell-Lagnado R, Zhu MX, Dong XP. 2015. Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion. J. Cell Biol. 209:879–94 [Google Scholar]
  15. Chen FW, Li C, Ioannou YA. 2010. Cyclodextrin induces calcium-dependent lysosomal exocytosis. PLOS ONE 5:e15054 [Google Scholar]
  16. Coen K, Flannagan RS, Baron S, Carraro-Lacroix LR, Wang D. et al. 2012. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198:23–35 [Google Scholar]
  17. Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE. et al. 2014. Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat. Neurosci. 17:1180–89 [Google Scholar]
  18. Cuervo AM, Dice JF. 2000. When lysosomes get old. Exp. Gerontol. 35:119–31 [Google Scholar]
  19. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. 2004. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305:1292–95 [Google Scholar]
  20. Curcio-Morelli C, Charles FA, Micsenyi MC, Cao Y, Venugopal B. et al. 2010. Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiol. Dis. 40:370–77 [Google Scholar]
  21. Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S. 2013. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79:447–60 [Google Scholar]
  22. Davies JP, Chen FW, Ioannou YA. 2000. Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290:2295–98 [Google Scholar]
  23. De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. 1955. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 60:604–17 [Google Scholar]
  24. de Pablo-Latorre R, Saide A, Polishhuck EV, Nusco E, Fraldi A, Ballabio A. 2012. Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases. Hum. Mol. Genet. 21:1770–81 [Google Scholar]
  25. Decressac M, Bjorklund A. 2013. TFEB: pathogenic role and therapeutic target in Parkinson disease. Autophagy 9:1244–46 [Google Scholar]
  26. Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A. 2013. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. PNAS 110:E1817–26 [Google Scholar]
  27. Di Malta C, Fryer JD, Settembre C, Ballabio A. 2012. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. PNAS 109:E2334–42 [Google Scholar]
  28. Dong XP, Wang X, Shen D, Chen S, Liu M. et al. 2009. Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. J. Biol. Chem. 284:32040–52 [Google Scholar]
  29. Enquist IB, Lo Bianco C, Ooka A, Nilsson E, Mansson JE. et al. 2007. Murine models of acute neuronopathic Gaucher disease. PNAS 104:17483–88 [Google Scholar]
  30. Eskelinen EL. 2006. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Asp. Med. 27:495–502 [Google Scholar]
  31. Fernandes Filho JA, Shapiro BE. 2004. Tay-Sachs disease. Arch. Neurol. 61:1466–68 [Google Scholar]
  32. Fraldi A, Annunziata F, Lombardi A, Kaiser HJ, Medina DL. et al. 2010. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 29:3607–20 [Google Scholar]
  33. Fraldi A, Hemsley K, Crawley A, Lombardi A, Lau A. et al. 2007. Functional correction of CNS lesions in an MPS-IIIA mouse model by intracerebral AAV-mediated delivery of sulfamidase and SUMF1 genes. Hum. Mol. Genet. 16:2693–702 [Google Scholar]
  34. Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K. et al. 2013. α-Synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLOS ONE 8:e62143 [Google Scholar]
  35. Futerman AH, van Meer G. 2004. The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol. 5:554–65 [Google Scholar]
  36. Geisler S, Holmstrom KM, Treis A, Skujat D, Weber SS. et al. 2010. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6:871–78 [Google Scholar]
  37. Graves AR, Curran PK, Smith CL, Mindell JA. 2008. The Cl/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453:788–92 [Google Scholar]
  38. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A. et al. 2013. Autophagosomes form at ER–mitochondria contact sites. Nature 495:389–93 [Google Scholar]
  39. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y. et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–89 [Google Scholar]
  40. Harris H, Rubinsztein DC. 2012. Control of autophagy as a therapy for neurodegenerative disease. Nat. Rev. Neurol. 8:108–17 [Google Scholar]
  41. Jardim LB, Villanueva MM, de Souza CF, Netto CB. 2010. Clinical aspects of neuropathic lysosomal storage disorders. J. Inherit. Metab. Dis. 33:315–29 [Google Scholar]
  42. Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L. et al. 2009. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137:60–72 [Google Scholar]
  43. Kalatzis V, Cherqui S, Antignac C, Gasnier B. 2001. Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter. EMBO J. 20:5940–49 [Google Scholar]
  44. Kilpatrick K, Zeng Y, Hancock T, Segatori L. 2015. Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein. PLOS ONE 10:e0120819 [Google Scholar]
  45. Kim HJ, Soyombo AA, Tjon-Kon-Sang S, So I, Muallem S. 2009. The Ca2+ channel TRPML3 regulates membrane trafficking and autophagy. Traffic 10:1157–67 [Google Scholar]
  46. Klein AD, Futerman AH. 2013. Lysosomal storage disorders: old diseases, present and future challenges. Pediatr. Endocrinol. Rev. 11:Suppl. 159–63 [Google Scholar]
  47. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J. et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84 [Google Scholar]
  48. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J. et al. 2007. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. PNAS 104:14489–94 [Google Scholar]
  49. Kramer ML, Schulz-Schaeffer WJ. 2007. Presynaptic α-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J. Neurosci. 27:1405–10 [Google Scholar]
  50. Kummel D, Ungermann C. 2014. Principles of membrane tethering and fusion in endosome and lysosome biogenesis. Curr. Opin. Cell Biol. 29:61–66 [Google Scholar]
  51. LaPlante JM, Sun M, Falardeau J, Dai D, Brown EM. et al. 2006. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89:339–48 [Google Scholar]
  52. Lee HJ, Khoshaghideh F, Patel S, Lee SJ. 2004. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24:1888–96 [Google Scholar]
  53. Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A. et al. 2015. Presenilin 1 maintains lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep. 12:1430–44 [Google Scholar]
  54. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS. et al. 2010. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141:1146–58 [Google Scholar]
  55. Lee S, Sato Y, Nixon RA. 2011. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J. Neurosci. 31:7817–30 [Google Scholar]
  56. Lee SM, Chin LS, Li L. 2012. Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. J. Cell Biol. 199:799–816 [Google Scholar]
  57. Li JQ, Tan L, Yu JT. 2014. The role of the LRRK2 gene in Parkinsonism. Mol. Neurodegener. 9:47 [Google Scholar]
  58. Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A. 2012. Autophagy in lysosomal storage disorders. Autophagy 8:719–30 [Google Scholar]
  59. Liu B, Du H, Rutkowski R, Gartner A, Wang X. 2012. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337:351–54 [Google Scholar]
  60. Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M. et al. 2015. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 160:177–90 [Google Scholar]
  61. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E. et al. 2008. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14:1247–55 [Google Scholar]
  62. Lopez ME, Klein AD, Dimbil UJ, Scott MP. 2011. Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder. J. Neurosci. 31:4367–78 [Google Scholar]
  63. Lundblad M, Decressac M, Mattsson B, Bjorklund A. 2012. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. PNAS 109:3213–19 [Google Scholar]
  64. Luzi P, Abraham RM, Rafi MA, Curtis M, Hooper DC, Wenger DA. 2009. Effects of treatments on inflammatory and apoptotic markers in the CNS of mice with globoid cell leukodystrophy. Brain Res. 1300:146–58 [Google Scholar]
  65. Macauley SL, Wong AM, Shyng C, Augner DP, Dearborn JT. et al. 2014. An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. J. Neurosci. 34:13077–82 [Google Scholar]
  66. Mak SK, McCormack AL, Manning-Bog AB, Cuervo AM, Di Monte DA. 2010. Lysosomal degradation of α-synuclein in vivo. J. Biol. Chem. 285:13621–29 [Google Scholar]
  67. March PA, Thrall MA, Brown DE, Mitchell TW, Lowenthal AC, Walkley SU. 1997. GABAergic neuroaxonal dystrophy and other cytopathological alterations in feline Niemann-Pick disease type C. Acta Neuropathol. 94:164–72 [Google Scholar]
  68. Martina JA, Chen Y, Gucek M, Puertollano R. 2012. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8:903–14 [Google Scholar]
  69. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J. et al. 2008. Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J. Clin. Investig. 118:777–88 [Google Scholar]
  70. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ. et al. 2011. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37–52 [Google Scholar]
  71. Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D. et al. 2015. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17:288–99 [Google Scholar]
  72. Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G. et al. 2011. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21:421–30 [Google Scholar]
  73. Menzies FM, Fleming A, Rubinsztein DC. 2015. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16:345–57 [Google Scholar]
  74. Micsenyi MC, Dobrenis K, Stephney G, Pickel J, Vanier MT. et al. 2009. Neuropathology of the Mcoln1−/− knockout mouse model of mucolipidosis type IV. J. Neuropathol. Exp. Neurol. 68:125–35 [Google Scholar]
  75. Mindell JA. 2012. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74:69–86 [Google Scholar]
  76. Mizushima N. 2007. Autophagy: process and function. Genes Dev. 21:2861–73 [Google Scholar]
  77. Moskot M, Montefusco S, Jakobkiewicz-Banecka J, Mozolewski P, Wegrzyn A. et al. 2014. The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J. Biol. Chem. 289:17054–69 [Google Scholar]
  78. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B. et al. 2010. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65:66–79 [Google Scholar]
  79. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S. et al. 2000. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–10 [Google Scholar]
  80. Nixon RA, Yang DS, Lee JH. 2008. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4:590–99 [Google Scholar]
  81. Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P. et al. 1999. α-Synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci. 19:5782–91 [Google Scholar]
  82. Palmieri M, Impey S, Kang H, di Ronza A, Pelz C. et al. 2011. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20:3852–66 [Google Scholar]
  83. Pastores GM, Maegawa GH. 2013. Clinical neurogenetics: neuropathic lysosomal storage disorders. Neurol. Clin. 31:1051–71 [Google Scholar]
  84. Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ. 2002. A role for α-synuclein in the regulation of dopamine biosynthesis. J. Neurosci. 22:3090–99 [Google Scholar]
  85. Platt FM, Boland B, van der Spoel AC. 2012. Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 199:723–34 [Google Scholar]
  86. Polito VA, Li H, Martini-Stoica H, Wang B, Yang L. et al. 2014. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol. Med. 6:1142–60 [Google Scholar]
  87. Rajendran L, Annaert W. 2012. Membrane trafficking pathways in Alzheimer's disease. Traffic 13:759–70 [Google Scholar]
  88. Rama Rao KV, Kielian T. 2016. Astrocytes and lysosomal storage diseases. Neuroscience 323195–206 [Google Scholar]
  89. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D. et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:1184–91 [Google Scholar]
  90. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C. et al. 2005. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37:771–76 [Google Scholar]
  91. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S. et al. 2004. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36:585–95 [Google Scholar]
  92. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J. et al. 2012. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5:ra42 [Google Scholar]
  93. Rogov V, Dotsch V, Johansen T, Kirkin V. 2014. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 53:167–78 [Google Scholar]
  94. Rong Y, McPhee CK, Deng S, Huang L, Chen L. et al. 2011. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. PNAS 108:7826–31 [Google Scholar]
  95. Rui YN, Xu Z, Patel B, Chen Z, Chen D. et al. 2015. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 17:262–75 [Google Scholar]
  96. Saez PJ, Orellana JA, Vega-Riveros N, Figueroa VA, Hernandez DE. et al. 2013. Disruption in connexin-based communication is associated with intracellular Ca2+ signal alterations in astrocytes from Niemann-Pick type C mice. PLOS ONE 8:e71361 [Google Scholar]
  97. Saftig P, Klumperman J. 2009. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10:623–35 [Google Scholar]
  98. Sagne C, Agulhon C, Ravassard P, Darmon M, Hamon M. et al. 2001. Identification and characterization of a lysosomal transporter for small neutral amino acids. PNAS 98:7206–11 [Google Scholar]
  99. Samie M, Wang X, Zhang X, Goschka A, Li X. et al. 2013. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev. Cell 26:511–24 [Google Scholar]
  100. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 2010. Ragulator–Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303 [Google Scholar]
  101. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC. et al. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–501 [Google Scholar]
  102. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M. et al. 2009. A gene network regulating lysosomal biogenesis and function. Science 325:473–77 [Google Scholar]
  103. Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ. 2007. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–8 [Google Scholar]
  104. Schulze H, Sandhoff K. 2011. Lysosomal lipid storage diseases. Cold Spring Harb. Perspect. Biol. 3:a004804 [Google Scholar]
  105. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F. et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 [Google Scholar]
  106. Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C. et al. 2008. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17:119–29 [Google Scholar]
  107. Settembre C, Fraldi A, Medina DL, Ballabio A. 2013. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14:283–96 [Google Scholar]
  108. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S. et al. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31:1095–108 [Google Scholar]
  109. Shachar T, Lo Bianco C, Recchia A, Wiessner C, Raas-Rothschild A, Futerman AH. 2011. Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond. Mov. Disord. 26:1593–604 [Google Scholar]
  110. Shen D, Wang X, Li X, Zhang X, Yao Z. et al. 2012. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat. Commun. 3:731 [Google Scholar]
  111. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G. et al. 2009. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361:1651–61 [Google Scholar]
  112. Siegel DA, Walkley SU. 1994. Growth of ectopic dendrites on cortical pyramidal neurons in neuronal storage diseases correlates with abnormal accumulation of GM2 ganglioside. J. Neurochem. 62:1852–62 [Google Scholar]
  113. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I. et al. 2009. Autophagy regulates lipid metabolism. Nature 458:1131–35 [Google Scholar]
  114. Song CY, Guo JF, Liu Y, Tang BS. 2012. Autophagy and its comprehensive impact on ALS. Int. J. Neurosci. 122:695–703 [Google Scholar]
  115. Song W, Wang F, Lotfi P, Sardiello M, Segatori L. 2014. 2-Hydroxypropyl-β-cyclodextrin promotes transcription factor EB-mediated activation of autophagy: implications for therapy. J. Biol. Chem. 289:10211–22 [Google Scholar]
  116. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. 1997. α-Synuclein in Lewy bodies. Nature 388:839–40 [Google Scholar]
  117. te Vruchte D, Lloyd-Evans E, Veldman RJ, Neville DC, Dwek RA. et al. 2004. Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J. Biol. Chem. 279:26167–75 [Google Scholar]
  118. Tian X, Gala U, Zhang Y, Shang W, Nagarkar Jaiswal S. et al. 2015. A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis. PLOS Biol. 13:e1002103 [Google Scholar]
  119. Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J. et al. 2012. PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci. Transl. Med. 4:142ra97 [Google Scholar]
  120. Vergarajauregui S, Connelly PS, Daniels MP, Puertollano R. 2008. Autophagic dysfunction in mucolipidosis type IV patients. Hum. Mol. Genet. 17:2723–37 [Google Scholar]
  121. Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC. et al. 1999. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat. Genet. 23:462–65 [Google Scholar]
  122. Vitner EB, Futerman AH, Platt N. 2015. Innate immune responses in the brain of sphingolipid lysosomal storage diseases. Biol. Chem. 396:659–67 [Google Scholar]
  123. Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M. et al. 2014. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat. Med. 20:204–8 [Google Scholar]
  124. Walker FO. 2007. Huntington's disease. Lancet 369:218–28 [Google Scholar]
  125. Wang W, Gao Q, Yang M, Zhang X, Yu L. et al. 2015. Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. PNAS 112:E1373–81 [Google Scholar]
  126. Williams IM, Wallom KL, Smith DA, Al Eisa N, Smith C, Platt FM. 2014. Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann–Pick disease type C1 mice. Neurobiol. Dis. 67:9–17 [Google Scholar]
  127. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE. et al. 2010. α-Synuclein impairs macroautophagy: implications for Parkinson's disease. J. Cell Biol. 190:1023–37 [Google Scholar]
  128. Wong E, Cuervo AM. 2010. Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci. 13:805–11 [Google Scholar]
  129. Wong YC, Holzbaur EL. 2014. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34:1293–305 [Google Scholar]
  130. Wu YP, Proia RL. 2004. Deletion of macrophage-inflammatory protein 1 α retards neurodegeneration in Sandhoff disease mice. PNAS 101:8425–30 [Google Scholar]
  131. Xu M, Liu K, Swaroop M, Porter FD, Sidhu R. et al. 2012. δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J. Biol. Chem. 287:39349–60 [Google Scholar]
  132. Yamamoto A, Cremona ML, Rothman JE. 2006. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172:719–31 [Google Scholar]
  133. Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, Beal MF. 2012. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J. Exp. Med. 209:2501–13 [Google Scholar]
  134. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y. et al. 2010. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–46 [Google Scholar]
  135. Yu T, Shakkottai VG, Chung C, Lieberman AP. 2011. Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. Hum. Mol. Genet. 20:4440–51 [Google Scholar]
  136. Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH. et al. 2011. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89:168–75 [Google Scholar]
  137. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M. et al. 2004. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–7 [Google Scholar]
  138. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. 2011. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334:678–83 [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