Pathophysiology of neuropathic lysosomal storage disorders
Tóm tắt
Although neurodegenerative diseases are most prevalent in the elderly, in rare cases, they can also affect children. Lysosomal storage diseases (LSDs) are a group of inherited metabolic neurodegenerative disorders due to deficiency of a specific protein integral to lysosomal function, such as enzymes or lysosomal components, or to errors in enzyme trafficking/targeting and defective function of nonenzymatic lysosomal proteins, all preventing the complete degradation and recycling of macromolecules. This primary metabolic event determines a cascade of secondary events, inducing LSD’s pathology. The accumulation of intermediate degradation affects the function of lysosomes and other cellular organelles. Accumulation begins in infancy and progressively worsens, often affecting several organs, including the central nervous system (CNS). Affected neurons may die through apoptosis or necrosis, although neuronal loss usually does not occur before advanced stages of the disease. CNS pathology causes mental retardation, progressive neurodegeneration, and premature death. Many of these features are also found in adult neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. However, the nature of the secondary events and their exact contribution to mental retardation and dementia remains largely unknown. Recently, lysosomal involvement in the pathogenesis of these disorders has been described. Improved knowledge of secondary events may have impact on diagnosis, staging, and follow-up of affected children. Importantly, new insights may provide indications about possible disease reversal upon treatment. A discussion about the CNS pathophysiology involvement in LSDs is the aim of this review. The lysosomal involvement in adult neurodegenerative diseases will also be briefly described.
Tài liệu tham khảo
Ausseil J, Desmaris N, Bigou S et al (2008) Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. PLoS ONE 3(5):e2296
Ayala A (2008) Insight into Parkinson’s Disease and α-Synuclein Degradation via the Lysosome: α-Synuclein Localization Changes in Vps28Δ. Eukaryon 4:107–111
Bagshaw RD, Mahuran DJ, Callahan JW (2005a) Lysosomal membrane proteomics and biogenesis of lysosomes. Mol Neurobiol 32:27–41
Bagshaw RD, Mahuran DJ, Callahan JW (2005b) A proteomic analysis of lysosomal integral membrane proteins reveals the diverse composition of the organelle. Mol Cell Proteomics 4(2):133–143
Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83:481–489
Bahr BA, Abai B, Gall CM, Vanderklish PW, Hoffman KB, Lynch G (1994) Induction of b-amyloid-containing polypeptides in hippocampus: Evidence for a concomitant loss of synaptic proteins and interactions with an excitotoxin. Exp Neurol 129:81–94
Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793:684–696
Barak V, Acker M, Nisman B et al (1999) Cytokines in Gaucher’s disease. Eur Cytokine Netw 10:205–210
Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529
Boot RG, Verhoek M, de Fost M et al (2004) Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 103:33–39
Boya P, Gonzalez-Polo RA, Casares N et al (2005) Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25:1025–1040
Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC (2003) Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22:8608–8618
Brown DA, London E (1998) Functions of lipid rafts in biological membranes. A Rev Cell Dev Biol 14:111–136
Brown DA, London E (2000) Structure and function of sphingolipid—and cholesterol-rich membrane rafts. J Biol Chem 275:17221–17224
Cao Y, Espinola JA, Fossale E et al (2006) Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem 281:20483–20493
Cataldo AM, Paskevich PA, Kominami E, Nixon RA (1991) Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci USA 88:10998–11002
Cataldo AM, Barnett JL, Berman SA et al (1995) Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14:671–680
Cataldo AM, Barnett JL, Mann DM, Nixon RA (1996) Colocalization of lysosomal hydrolase and beta-amyloid in diffuse plaques of the cerebellum and striatum in Alzheimer’s disease and Down’s syndrome. J Neuropathol Exp Neurol 55:704–715
Cataldo AM, Barnett JL, Pieroni C, Nixon RA (1997) Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci 17:6142–6151
Cataldo AM, Peterhoff CM, Schmidt SD, Terio NB, Duff K, Beard M (2004) Presenilin mutations in familial Alzheimer disease and transgenic mice models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol 63:821–830
Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson's disease: Relationship to alpha-synuclein inclusions. Neurobiol Dis 35:385–398
Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6:889–898
Cooper JD, Russell C, Mitchison HM (2006) Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1762:873–889
Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295
D’Azzo A, Tessitore A, Sano R (2006) Gangliosides as apoptotic signals in ER stress response. Cell Death Differ 13:404–413
Dermine JF, Duclos S, Garin J et al (2001) Flotillin-1-enriched lipid raft domains accumulate on maturing phagosomes. J Biol Chem 276:18507–18512
Desnick RJ, Thorpe SR, Fiddler M (1976) Toward enzyme therapy for lysosomal storage diseases. Physiol Rev 56:57–99
Di Fonzo A, Chien HF, Socal M et al (2007) ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology 68:1557–1562
Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, Figura K, Schmidt B (2009) Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease—Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta 1793:710–725
Duyckaerts C, Dickson DW (2003) Neuropathology of Alzheimer’s disease. In: Dickson D (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 47–65
Dyer RB, McMurray CT (2001) Mutant protein in Huntington disease is resistant to proteolysis in affected brain. Nat Genet 29:270–278
Eskelinen EL, Saftig P (2009) Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793:664–673
Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 101:890–898
Farfel-Becker T, Vitner E, Dekel H, Leshem N, Enquist IB, Karlsson S, Futerman AH (2009) No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease. Hum Mol Genet 18:1482–1488
Feinstein SC, Wilson L (2005) Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochim Biophys Acta 1739:268–279
Feng B, Yao PM, Li Y et al (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5:781–792
Fill M, Copello JA (2002) Ryanodine receptor calcium release channels. Physiol Rev 82:893–922
Fortun J, Dunn WA Jr, Joy S, Li J, Notterpek L (2003) Emerging role for autophagy in the removal of aggresomes in Schwann cells. J Neurosci 23:10672–10680
Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554–565
German DC, Liang CL, Song T, Yazdani U, Xie C, Dietschy JM (2002) Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109:437–450
Gieselmann V, Franken S, Klein D et al (2003) Metachromatic leukodystrophy: consequences of sulphatide accumulation. Acta Paediatr Suppl 92:74–79
Ginzburg L, Futerman AH (2005) Defective calcium homeostasis in the cerebellum in a mouse model of Niemann-Pick A disease. J Neurochem 95:1619–1628
Ginzburg L, Kacher Y, Futerman AH (2004) The pathogenesis of glycosphingolipid storage disorders. Semin Cell Dev Biol 15(4):417–431
Ginzburg L, Li SC, Li YT, Futerman AH (2008) An exposed carboxyl group on sialic acid is essential for gangliosides to inhibit calcium uptake via the sarco/endoplasmic reticulum Ca2+−ATPase: relevance to gangliosidoses. J Neurochem 104:140–146
Goebel HH, Schochet SS, Jaynes M, Bruck W, Kohlschutter A, Hentati F (1999) Progress in neuropathology of the neuronal ceroid lipofuscinoses. Mol Genet Metab 66:367–372
Gruenberg J (2001) The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol 2:721–730
Hamano T, Gendron TF, Causevic et al (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci 27:1119–1130
Hayashi M (2009) Oxidative stress in developmental brain disorders. Neuropathology 29:1–8
Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889
Hers HG (1965) Progress in gastroenterology: Inborn lysosomal diseases. Gastroenterology 48:625–633
Hers HG, Van Hoof F (1973) Lysosomes and storage diseases. Academic Press, New York
Hollak CE, Evers L, Aerts JM, van Oers MH (1997) Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood Cells Mol Dis 23:201–212
Jaeger PA, Wyss-Coray T (2009) All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 4:16
Jennings JJ, Zhu JH Jr, Rbaibi Y, Luo X, Chu CT, Kiselyov K (2006) Mitochondrial aberrations in mucolipidosis Type IV. J Biol Chem 281:39041–39050
Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725
Jeyakumar M, Williamsa I, Smitha DA, Coxb TM, Platt FM (2009) Critical role of iron in the pathogenesis of the murine gangliosidoses. Neurobiol dis 34:406–416
Johnson GV (2006) Tau phosphorylation and proteolysis: insights and perspectives. J Alzheimer’s Dis 9:243–250
Jolly RD, Brown S, Das AM, Walkley SU (2002) Mitochondrial dysfunction in the neuronal ceroidlipofuscinoses (Batten disease). Neurochem Int 40:565–571
Journet A, Chapel A, Kieffer S, Roux F, Garin J (2002) Proteomic analysis of human lysosomes: application to monocytic and breast cancer cells. Proteomics 2:1026–1040
Kacher Y, Futerman AH (2006) Genetic diseases of sphingolipid metabolism: Pathological mechanisms and therapeutic options. FEBS Lett 580:5510–5517
Kasahara K, Sanai Y (2000) Functional roles of glycosphingolipids in signal transduction via lipid rafts. Glycoconj J 17:153–162
Kay GW, Palmer DN, Rezaie P, Cooper JD (2006) Activation of non-neuronal cells within the prenatal developing brain of sheep with neuronal ceroid lipofuscinosis. Brain Pathol 16:110–116
Kawashita E, Tsuji D, Kawashima N, Nakayama K, Matsuno H, Itoh K (2009) Abnormal production of macrophage inflammatory protein-1alpha by microglial cell lines derived from neonatal brains of Sandhoff disease model mice. J Neurochem 109:1215–1224
Kegel KB, Kim M, Sapp E et al (2000) Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci 20:7268–7278
Kielar C, Maddox L, Bible E et al (2007) Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 25:150–162
Kiselyov K, Muallem S (2008) Mitochondrial Ca2+ homeostasis in lysosomal storage diseases. Cell Calcium 44:103–111
Kiselyov K, Jennigs JJ Jr, Rbaibi Y, Chu CT (2007) Autophagy, Mitochondria and Cell Death in Lysosomal Storage Diseases. Autophagy 3:259–262
Klionsky DJ (2005) The molecular machinery of autophagy: unanswered questions. J Cell Sci 118:7–18
Koike M, Shibata M, Waguri S et al (2005) Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol 167:1713–1728
Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884
Kornfeld S, Sly WS (2001) I-cell disease and pseudo-Hurler polydystrophy: disorders of lysosomal enzyme phosphorylation and localization. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds.) Childs B
Korkotian E, Schwarz A, Pelled D, Schwarzmann G, Segal M, Futerman AH (1999) Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem 274:21673–21678
Larsen KE, Sulzer D (2002) Autophagy in neurons: a review. Histol Histopathol 17:897–908
Ledeen RW, Yu RK (1982) Gangliosides: structure, isolation and analysis. Methods Enzymol 83:139–191
Lee JA, Gao FB (2009) Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J Neurosci 29:8506–8511
Lee HJ, Khoshaghideh F, Patel S, Lee SJ (2004) Clearance of alpha-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci 24:1888–1896
Lee DW, Andersen JK, Kaur D (2006) Iron Dysregulation and Neurodegeneration: The Molecular Connection. Mol Interv 6:89–97
Li HH, Zhao HZ, Neufeld EF, Cai Y, Gomez-Pinilla F (2002) Attenuated plasticity in neurons and astrocytes in the mouse model of Sanfilippo syndrome type B. J Neurosci Res 69:30–38
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
Lin F, Wu J, Wang Y, Qin Z (2007) Huntingtin cleavage induced by thrombin in vitro. Acta Biochim Biophys Sin (Shanghai) 39(1):15–18
Ling EA, Wong WC (1993) The origin and nature of ramified and amoeboid microglia: a historical review and current concepts. Glia 7:9–18
Lloyd-Evans E, Pelled D, Riebeling C et al (2003) Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms. J Biol Chem 278:23594–23599
Lloyd-Evans E, Morgan AJ, He X et al (2008) Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14:1247–1255
Lübke T, Lobel P, Sleat DE (2009) Proteomics of the lysosome. Biochim Biophys Acta 1793:625–635
Lucke T, Hoppner W, Schmidt E, Illsinger S, Das AM (2004) Fabry disease: reduced activities of respiratory chain enzymes with decreased levels of energy-rich phosphates in fibroblasts. Mol Genet Metab 82:93–97
Malkus KA, Tsika E, Ischiropoulos H (2009) Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle. Mol Neurodegener 4:24
Mancuso C, Scapagini G, Curro D, Giuffrida Stella AM, De Marco C, Butterfield DA, Calabrese V (2007) Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front Biosci 12:1107–1123
March PA, Thrall MA, Wurzelmann S, Brown D, Walkley SU (1997) Dendritic and axonal abnormalities in feline Niemann-Pick disease type C. Acta Neuropathol 94:164–172
Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350
Meijer AJ, Codogno P (2009) Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci 46:210–240
Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. Jama 281:249–254
Meredith GE, Totterdell S, Petroske E, Santa Cruz K, Callison RC, Lau YS (2002) Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease. Brain Res 956:156–165
Mielke JG, Murphy MP, Maritz J, Bengualid KM, Ivy GO (1997) Chloroquine administration in mice increases b-amyloid immunoreactivity and attenuates kainate-induced blood-brain barrier dysfunction. Neurosci Lett 227:169–172
Misquitta CM, Mack DP, Grover AK (1999) Sarco/endoplasmic reticulum Ca2+ (SERCA)-pumps: link to heart beats and calcium waves. Cell Calcium 25:277–290
Mitchison HM, Lim MJ, Cooper JD (2004) Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol 14:86–96
Mole SE, Williams RE, Goebel HH (2005) Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6:107–126
Moos T, Morgan EH (2004) The metabolism of neuronal iron and its pathogenic role in neurological disease: Review. Ann NY Acad Sci 1012:14–26
Nadadur SS, Srirama K, Mudipalli A (2008) Iron transport & homeostasis mechanisms: their role in health & disease. Indian J Med Res 128:533–544
Nguyen HN, Wang C, Perry DC (2002) Depletion of intracellular calcium stores is toxic to SH-SY5Y neuronal cells. Brain Res 924:159–166
Nixon RA, Mathews PM, Cataldo AM (2001) The neuronal endosomal-lysosomal system in Alzheimer’s disease. J Alzheimer’s Dis 3:97–107
Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci USA 100:1902–1907
Ohmi K, Kudo LC, Ryazantsev S, Zhao HZ, Karstenb SL, Neufelda EF (2009) Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proc Natl Acad Sci USA 106:8332–8337
Overly CC, Hollenbeck PJ (1996) Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons. J Neurosci 16:6056–6064
Pagano RE (2003) Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases. Philos Trans R Soc Lond B Biol Sci 358:885–891
Pagano RE, Puri V, Dominguez M, Marks DL (2000) Membrane traffic in sphingolipid storage diseases. Traffic 1:807–815
Pan T, Kondo S, Le W, Jankovic J (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131:1969–1978
Papanikolaou G, Pantopoulos K (2005) Iron metabolism and toxicity. Toxicol Appl Pharmacol 202:199–211
Pelled D, Lloyd-Evans E, Riebeling C, Jeyakumar M, Platt FM, Futerman AH (2003) Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase in a mouse model of Sandhoff disease and prevention by treatment with Nbutyldeoxynojirimycin. J Biol Chem 278:29496–29501
Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH (2005) Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 18:83–88
Platt FM, Walkley SU (2004) Lysosomal defects and storage. In: Platt FM, Walkley SU (eds) Lysosomal Disorders of the Brain: Recent Advances in Molecular and Cellular Pathogenesis and Treatment, 1st edn. Oxford University Press, New York, pp 32–49
Platt FM, Lachmann RH (2009) Treating lysosomal storage disorders: Current practice and future prospects. Biochim Biophys Acta 1793:737–745
Pontikis CC, Cella CV, Parihar N et al (2004) Late onset neurodegeneration in the Cln3-/−mouse model of juvenile neuronal ceroid lipofuscinosis is preceded by low level glial activation. Brain Res 1023:231–242
Proia R, Wu YP (2004) Blood to brain to the rescue. J Clinl Invest 113:1108–1110
Qin ZH, Wang YM, Kegel KB et al (2003) Autophagy regulates the processing of amino terminal huntingtin fragments. Hum Mol Genet 12:3231–3244
Qin ZH, Wang YM, Sapp E et al (2004) b) Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci 24:269–281
Raben RN, Shea L, Hill V, Plotz P (2009) Monitoring autophagy in lysosomal storage disorders. Methods Enzymol 453:417–449
Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117
Roisen FJ, Bartfeld H, Nagele R, Yorke G (1981) Ganglioside stimulation of axonal sprouting in vitro. Science 214:577–578
Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–786
Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6(4):304–312
Santavuori P, Haltia M, Rapola J, Raitta C (1973) Infantile type of so-called neuronal ceroid-lipofuscinosis. 1. A clinical study of 15 patients. J Neurol Sci 18:257–267
Sardiello M, Palmieri M, di Ronza A et al (2009) A Gene Network Regulating Lysosomal Biogenesis and Function. Science 325:473–477
Schapira AH (2009) Etiology and pathogenesis of Parkinson disease. Neurol Clin 27:583–603
Settembre C, Annunziata I, Spampanato C et al (2007) Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency. Pro Natl Acad Sci USA 104:4506–4511
Settembre C, Fraldi A, Jahreiss L et al (2008) A Block of Autophagy in Lysosomal Storage Disorders. Hum Mol Genet 17:119–129
Shacka JJ, Roth KA (2005) Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implications. Curr Drug Targets CNS Neurol Disord 4(1):25–39. Review
Sharma DK, Choudhury A, Singh RD, Wheatley CL, Marks DL, Pagano RE (2003) Glycosphingolipids internalized via caveolar-related endocytosis rapidly merge with the clathrin pathway in early endosomes and form microdomains for recycling. J Biol Chem 278:7564–7572
Shimura H, Schwartz D, Gygi SP, Kosik KS (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–4876
Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 5698:990–995
Silva LC, Futerman AH, Prieto M (2009) Lipid raft composition modulates sphingomyelinase activity and ceramide-induced membrane physical alterations. Biophys J 96:3210–3222
Sipe JC, Lee P, Beutler E (2002) Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24:188–196
Smith D, Wallom KL, Williams IM, Jeyakumar M, Platt FM (2009) Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiol Dis 36:242–251
Streit WJ, Graeber MB, Kreutzberg GW (1988) Functional plasticity of microglia: a review. Glia 1:301–307
Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging [Epub ahead of print]
Tardy C, Andrieu-Abadie N, Salvayre R, Levade T (2004) Lysosomal storage diseases: is impaired apoptosis a pathogenic mechanism? Neurochem Res 29:871–880
Terman A, Gustafsson B, Brunk UT (2006) The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 163:29–37
Tessitore A, Pirozzi M, Auricchio A (2009) Abnormal autophagy, ubiquitination, inflammation and apoptosis are dependent upon lysosomal storage and are useful biomarkers of mucopolysaccharidosis VI. Pathogenetics 2:4
Tooze SA, Schiavo G (2008) Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr Opin Neurobiol 18:504–515
Uchiyama Y, Koike M, Shibata M, Sasaki M (2009) Autophagic neuron death. Methods Enzymol 453:33–51
Vellodi A (2004) Lysosomal storage disorders. Br J Haematol 128:413–431
Villani GR, Gargiulo N, Faraonio R et al (2007) Cytokines, neurotrophins, and oxidative stress in brain disease from mucopolysaccharidosis IIIB. J Neurosci Res 85:612–622
Villani GR, Di Domenico C, Musella A, Cecere F, Di Napoli D, Di Natale P (2009) Mucopolysaccharidosis IIIB: oxidative damage and cytotoxic cell involvement in the neuronal pathogenesis. Brain Res 1279:99–108
Visigalli I, Moresco RM, Belloli S et al (2009) Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195. Neurobiol Dis 34:51–62
Wada R, Tifft CJ, Proia RL (2000) Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proc Natl Acad Sci USA 97:10954–10959
Walkley SU (1998) Cellular Pathology of Lysosomal Storage Disorders. Brain Pathol 8:175–193
Walkley SU (2004a) Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol 15:433–444
Walkley SU (2004 b) Pathogenic cascades and brain dysfunction. In: Platt FM, Walkley SU (eds.) Lysosomal disorders of the brain. Oxford University Press, pp. 32–49
Walkley SU (2007) Pathogenic mechanisms in lysosomal disease: a reappraisal of the role of the lysosomes. Acta Paediatr 96:26–32
Walkley SU (2009) Pathogenic cascades in lysosomal disease—Why so complex? J Inherit Metab Dis 32:181–189
Walkley SU, March PA (1993) Biology of Neuronal Dysfunction in Storage Disorders. J Inherit Metab Dis 16:284–287
Walkley SU, Suzuki K (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 1685:48–62
Walkley SU, Vanier MT (2009) Secondary lipid accumulation in lysosomal disease. Biochim Biophys Acta 1793:726–736
Walkley SU, Baker HJ, Rattazzi MC, Haskins ME, Wu J-Y (1991) Neuroaxonal dystrophy in neuronal storage disorders: Evidence for major GABAergic neuron involvement. J Neurol Sci 104:1–8
Walkley SU, Thrall MA, Haskins ME et al (2005) Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease. Neuropathol Appl Neurobiol 31:536–544
Wellingtona CL, Ellerbyb LM, Leavittc BR, Royd S, Nicholsond DW, Haydenc MR (2003) Huntingtin proteolysis in Huntington disease. Clin Neurosci Res 3:129–139
Wei H, Kim SJ, Zhang Z, Tsai PC, Wisniewski KE, Mukherjee AB (2008) ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum Mol Genet 17:469–477
Winslow AR, Rubinsztein DC (2008) Autophagy in neurodegeneration and development. Biochim Biophys Acta 1782:723–729
Woloszynek JC, Coleman T, Semenkovich CF, Sands (2007) MSJ Biol Chem 282:35765–35771
Woloszynek JC, Kovacs A, Ohlemiller KK, Roberts M, Sands (2009) Metabolic adaptations to interrupted glycosaminoglycan recycling. MSJ Biol Chem 284:29684–29691
Wong ES, Tan JM, Soong WE et al (2008) Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet 17:2570–2582
Wraith JE (2004) Clinical aspects and diagnosis. In: Platt FM, Walkley SU (eds) Lysosomal Disorders of the Brain. Oxford University Press, Oxford, pp 50–77
Wu YP, Proia RL (2004) Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proc Natl Acad Sci USA 101:8425–8430
Wu J, Lin F, Qin Z (2007) Sequestration of glyceraldehyde-3-phosphate dehydrogenase to aggregates formed by mutant huntingtin. Acta Biochim Biophys Sin (Shanghai) 39(11):885–890
Xu GG, Deng YQ, Liu SJ, Li HL, Wang JZ (2005) Prolonged Alzheimer-like Tau hyperphosphorylation induced by simultaneous inhibition of phosphoinositol-3 kinase and protein kinase C in N2a cells. Acta Biochim Biophys Sin (Shanghai) 37(5):349–354
Zhang L, Sheng R, Qin Z (2009) The lysosome and neurodegenerative diseases. Acta Biochim Biophys Sin (Shanghai) 41:437–445