한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제13권2호
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  • Pages.63-77
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  • 2009
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  • 2465-9525(pISSN)
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  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
권호 표지

유전질환 신경 세로이드 리포푸신증들에 대한 고찰

Genetic and Molecular Mechanisms in the Neuronal Ceroid-Lipofuscinoses

  • 이민영 (호서대학교 생명공학과) ;
  • 김동현 (호서대학교 생명공학과) ;
  • 윤동호 (호서대학교 생명공학과) ;
  • 김한복 (호서대학교 생명공학과) ;
  • 박주훈 (호서대학교 본초응용과학과) ;
  • 이환명 (호서대학교 본초응용과학과) ;
  • 김성훈 (경희대학교 한의과대학 암예방소재개발연구센터) ;
  • 김성조 (호서대학교 생명공학과)
  • 발행 : 2009.06.30
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⟨ 이전 논문 다음 논문 ⟩

초록

신경리포푸신증(NCLs)은 신경퇴행 축적 질환으로 뇌에 자기형광물질을 포함한 다양한 물질의 축적이 야기되어 발생하며, 노던에필렙시를 제외한 모든 신경포푸신증은 리소즘 축적 질환으로 분류된다. 이러한 신경리포푸신증은 전세계적으로 12,500명 중 1명에게 발생되는 높은 발병 빈도를 나타내며, 그 발병 시기에 따라 영아형, 영유아형, 유년형, 그리고 성인형과 같이 분류된다. 신경리포푸신증이 유발하는 의학적 증상로는 시각 손실, 발작, 간질, 진행성 정신지체등을 야기하여 소아성 치매라는 이야기를 들으며, 증상이 심할 경우 환자가 사망에 이르게 된다. 신경퇴행성 리포푸신증의 원인은 유전자의 돌연변이 때문이라고 알려져 있으며, 일부의 연구를 통해 태아의 발생과정 상 문제를 통해 질병이 야기되는 경우도 관찰이 되고 있으나, 아직 그 분자 발생학적 기전이 명확하게 규명되어 있지 않은 현실이다. 현재 전 세계적으로 많은 연구가 수행되고 있어 그 결과가 주목되는 바이다.

The neuronal ceroid-lipofuscinoses (NCLs) are a kind of neurodegenerative storage disorders. The NCLs are charecterizated by accumulation of autofluorescent lipofuscin or lipopigment in the brain. All NCL group belongs to in lysosomal storage disorders (LSDs), except Northern epilepsy. NCLs are the most common group of progressive neurodegenerative disorders in childhood, with an incidence as high as I in 12,500 live births. Four main clinical types have been described based on the onset age : infantile, late infantile, juvenile and adult types. Clinical symptoms of NCLs include loss of vision, seizures, epilepsy, progressive mental retardation and a premature death. Although mutation causes neurodegeneration in NCLs, the molecular mechanism by which mutation leads to neurodegeneration remains unclear. In this paper, we review the characteristics of these NCLs.

키워드

참고문헌

  1. Ahtiainen L, Kolikova J, Mutka AL, Luiro K, Gentile M, Ikonen E, Khiroug L, Jalanko A, Kopra O (2007) Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction. Neurobiol Dis 28:52-64. https://doi.org/10.1016/j.nbd.2007.06.012
  2. Benedict JW, Sommers CA, Pearce DA (2007) Progressive oxidative damage in the central nervous system of a murine model for juvenile Batten disease. J Neurosci Res 85:2882-2891. https://doi.org/10.1002/jnr.21416
  3. Boustany RM (1992) Neurology of the neuronal ceroidlipofuscinoses: late infantile and juvenile types. Am J Med Genet 42:533-535. https://doi.org/10.1002/ajmg.1320420421
  4. Boustany RM, Filipek P (1993) Seizures, depression and dementia in teenagers with Batten disease. J Inherit Metab Dis 16:252-255. https://doi.org/10.1007/BF00710257
  5. Buff H, Smith AC, Korey CA (2007) Genetic modifiers of Drosophila palmitoyl-protein thioesterase 1-induced degeneration. Genetics 176:209-220. https://doi.org/10.1534/genetics.106.067983
  6. Carpenter S, Karpati G (1986) Lysosomal storage in human skeletal muscle. Hum Pathol 17:683-703. https://doi.org/10.1016/S0046-8177(86)80179-4
  7. Cooper JD, Russell C, Mitchison HM (2006) Progress towards understanding disease mechanisms in small verte brate models of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1762:873-889. https://doi.org/10.1016/j.bbadis.2006.08.002
  8. Cotman SL, Vrbanac V, Lebel LA, Lee RL, Johnson KA, Donahue LR, Teed AM, Antonellis K, Bronson RT, Lerner TJ and others (2002) Cln3(Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet 11:2709-2721. https://doi.org/10.1093/hmg/11.22.2709
  9. Elleder M, Dvorakova L, Stolnaja L, Vlaskova H, Hulkova H, Druga R, Poupetova H, Kostalova E, Mikulastik J (2008) Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency. Acta Neuropathol 116:119-124. https://doi.org/10.1007/s00401-008-0349-3
  10. Ezaki J, Takeda-Ezaki M, Koike M, Ohsawa Y, Taka H, Mineki R, Murayama K, Uchiyama Y, Ueno T, Kominami E (2003) Characterization of Cln3p, the gene product responsible for juvenile neuronal ceroid lipofuscinosis, as a lysosomal integral membrane glycoprotein. J Neurochem 87:1296-1308. https://doi.org/10.1046/j.1471-4159.2003.02132.x
  11. Fossale E, Wolf P, Espinola JA, Lubicz-Nawrocka T, Teed AM, Gao H, Rigamonti D, Cattaneo E, MacDonald ME, Cotman SL (2004) Membrane trafficking and mitochondrial abnonnalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMC Neurosci 5:57. https://doi.org/10.1186/1471-2202-5-57
  12. Fritchie K, Siintola E, Armao D, Lehesjoki AE, Marino T, Powell C, Tennison M, Booker JM, Koch S, Partanen S and others (2009) Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 117:201-208. https://doi.org/10.1007/s00401-008-0426-7
  13. Frugier T, Mitchell NL, Tammen I, Houweling PJ, Arthur DG, Kay GW, van Diggelen OP, Jolly RD, Palmer DN (2008) A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3. Neurobiol Dis 29:306-315. https://doi.org/10.1016/j.nbd.2007.09.006
  14. Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell BioI 5:554-565. https://doi.org/10.1038/nrm1423
  15. Gdynia HJ, Sperfeld AD, Ludolph AC (2007) Adult-onset neuronal ceroid lipofuscinosis. Nervenarzt 78: 139-140, 142-144.
  16. Goebel HH (1995) The neuronal ceroid-lipofuscinoses. J Child Neurol 10:424-437. https://doi.org/10.1177/088307389501000602
  17. Goebel HH, Kominami E, Neuen-Jacob E, Wheeler RB (2001) Morphological studies on CLN2. Eur J Paediatr Neurol 5 Suppl A:203-207.
  18. Golabek AA, Kaczmarski W, Kida E, Kaczmarski A, Michalewski MP, Wisniewski KE (1999) Expression studies of CLN3 protein (battenin) in fusion with the green fluorescent protein in mammalian cells in vitro. Mol Genet Metab 66:277-282. https://doi.org/10.1006/mgme.1999.2836
  19. Gupta P, Soyombo AA, Atashband A, Wisniewski KE, Shelton JM, Richardson JA, Hammer RE, Hofinann SL (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci USA 98:13566-13571. https://doi.org/10.1073/pnas.251485198
  20. Haines JL, Boustany RM, Alroy J, Auger KJ, Shook KS, Terwedow H, Lerner TJ (1998) Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis. Neurogenetics 1:217-222. https://doi.org/10.1007/s100480050032
  21. Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 193:279-290. https://doi.org/10.1016/j.expneurol.2005.01.013
  22. Haltia M (2006) The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta 1762:850-856. https://doi.org/10.1016/j.bbadis.2006.06.010
  23. Haltia M, Herva R, Suopanki J, Baumann M, Tyynela J (2001) Hippocampal lesions in the neuronal ceroid lipofuscinoses. Eur J Paediatr Neurol 5 Suppl A:209-211. https://doi.org/10.1053/eipn.2000.0464
  24. Haskell RE, Carr CJ, Pearce DA, Bennett MJ, Davidson BL (2000) Batten disease: evaluation of CLN3 mutations on protein localization and function. Hum Mol Genet 9:735-744. https://doi.org/10.1093/hmg/9.5.735
  25. Heine C, Tyynela J, Cooper JD, Palmer DN, Elleder M, Kohlschutter A, Braulke T (2003) Enhanced expression of manganese-dependent superoxide dismutase in human and sheep CLN6 tissues. Biochem J 376:369-376. https://doi.org/10.1042/BJ20030598
  26. Herva R, Tyynela J, Hirvasniemi A, SyIjakallio-Ylitalo M, Haltia M (2000) Northem epilepsy: a novel form of neuronal ceroid-lipofuscinosis. Brain Pathol 10:215-222. https://doi.org/10.1111/j.1750-3639.2000.tb00255.x
  27. Hobert JA, Dawson G (2006) Neuronal ceroid lipofuscinoses therapeutic strategies: past, present and future. Biochim Biophys Acta 1762:945-953. https://doi.org/10.1016/j.bbadis.2006.08.004
  28. Isosomppi J, Vesa J, Jalanko A, Peltonen L (2002) Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. Hum Mol Genet 11:885-891. https://doi.org/10.1093/hmg/11.8.885
  29. Jalanko A, Vesa J, Manninen T, von Schantz C, Minye H, Fabritius AL, Salonen T, Rapola J, Gentile M, Kopra O and others (2005) Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiol Dis 18:226-241. https://doi.org/10.1016/j.nbd.2004.08.013
  30. Janes RW, Munroe PB, Mitchison HM, Gardiner RM, Mole SE, Wallace BA (1996) A model for Batten disease protein CLN3: functional implications from homology and mutations. FEBS Lett 399:75-77. https://doi.org/10.1016/S0014-5793(96)01290-2
  31. Jarvela I, Lehtovirta M, Tikkanen R, Kyttala A, Jalanko A (1999) Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Hum Mol Genet 8:1091-1098. https://doi.org/10.1093/hmg/8.6.1091
  32. Jarvela I, Sainio M, Rantamaki T, Olkkonen VM, Carpen O, Peltonen L, Jalanko A (1998) Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Hum Mol Genet 7:85-90. https://doi.org/10.1093/hmg/7.1.85
  33. Kaczmarski W, Wisniewski KE, Golabek A, Kaczmarski A, Kida E, Michalewski M (1999) Studies of membrane association of CLN3 protein. Mol Genet Metab 66:261-264. https://doi.org/10.1006/mgme.1999.2833
  34. Kalviainen R, Eriksson K, Losekoot M, Sorri I, Harvima I, Santavuori P, Jarvela I, Autti T, Vanninen R, Salmenpera T and others (2007) Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoylprotein thioesterase deficiency. Eur J Neurol 14:369-372. https://doi.org/10.1111/j.1468-1331.2007.01668.x
  35. Katz ML, Gao CL, Prabhakaram M, Shibuya H, Liu PC, Johnson GS (1997) Immunochemicallocalization of the Batten disease (CLN3) protein in retina. Invest Ophthalmol Vis Sci 38:2375-2386.
  36. Kida E, Kaczmarski W, Golabek AA, Kaczmarski A, Michalewski M, Wisniewski KE (1999) Analysis of intracellular distribution and trafficking of the CLN3 protein in fusion with the green fluorescent protein in vitro. Mol Genet Metab 66:265-271. https://doi.org/10.1006/mgme.1999.2837
  37. Kim SJ, Zhang Z, Hitomi E, Lee YC, MukheIjee AB (2006a) Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. Hum Mol Genet 15:1826-1834. https://doi.org/10.1093/hmg/ddl105
  38. Kim SJ, Zhang Z, Lee YC, MukheIjee AB (2006b) Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Hum Mol Genet 15:1580-1586. https://doi.org/10.1093/hmg/ddl078
  39. Kim SJ, Zhang Z, Sarkar C, Tsai PC, Lee YC, Dye L, MukheIjee AB (2008) Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice. J Clin Invest 118:3075-3086. https://doi.org/10.1172/JCI33482
  40. Klockars T, Savukoski M, Isosomppi J, Peltonen L (1999) Positional cloning of the CLN5 gene defective in the Finnish variant of the LINCL. Mol Genet Metab 66: 324-328. https://doi.org/10.1006/mgme.1999.2832
  41. Kopra O, Vesa J, von Schantz C, Manninen T, Minye H, Fabritius AL, Rapola J, van Diggelen OP, Saarela J, Jalanko A and others (2004) A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Hum Mol Genet 13:2893-2906. https://doi.org/10.1093/hmg/ddh312
  42. Kremmidiotis G, Lensink. IL, Bilton RL, Woollatt E, Chataway TK, Sutherland GR, Callen DF (1999) The Batten disease gene product (CLN3p) is a Golgi integral membrane protein. Hum Mol Genet 8:523-531. https://doi.org/10.1093/hmg/8.3.523
  43. Kyttala A, Lahtinen U, Braulke T, Hofmann SL (2006) Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins. Biochim Biophys Acta 1762:920-933. https://doi.org/10.1016/j.bbadis.2006.05.007
  44. Lofgren E, Pouta A, von Wendt L, Tapanainen J, Isojarvi JI, Jarvelin MR (2009) Epilepsy in the northern Finland birth cohort 1966 with special reference to fertility. Epilepsy Behav 14:102-107. https://doi.org/10.1016/j.yebeh.2008.08.007
  45. Lou HC, Kristensen K (1973) A clinical and psychological investigation into juvenile amaurotic idiocy in Denmark. Dev Med Child Neurol 15:313-323. https://doi.org/10.1111/j.1469-8749.1973.tb04888.x
  46. Luiro K, Kopra O, Blom T, Gentile M, Mitchison HM, Hovatta I, Tornquist K, Jalanko A (2006) Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments. J Neurosci Res 84:1124-1138. https://doi.org/10.1002/jnr.21015
  47. Luiro K, Kopra O, Lehtovirta M, Jalanko A (2001) CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. Hum Mol Genet 10:2123-2131. https://doi.org/10.1093/hmg/10.19.2123
  48. Mitchison HM, Mole SE (2001) Neurodegenerative disease: the neuronal ceroid lipofuscinoses (Batten disease). Curr Opin Neurol 14:795-803. https://doi.org/10.1097/00019052-200112000-00019
  49. Mole SE, Mitchison HM, Munroe PB (1999) Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Hum Mutat 14:199-215. https://doi.org/10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A
  50. Mole SE, Williams RE, Goebel HH (2005) Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6:107-126. https://doi.org/10.1007/s10048-005-0218-3
  51. Moore SJ, Buckley DJ, MacMillan A, Marshall HD, Steele L, Ray PN, Nawaz Z, Baskin B, Frecker M, Carr SM and others (2008) The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin Genet 74:213-222. https://doi.org/10.1111/j.1399-0004.2008.01054.x
  52. Narayan SB, Pastor JV, Mitchison HM, Bennett MJ (2004) CLN3L, a novel protein related to the Batten disease protein, is overexpressed in Cln3-/- mice and in Batten disease. Brain 127:1748-1754. https://doi.org/10.1093/brain/awh195
  53. Pearce DA, Sherman F (1997) BTN1, a yeast gene corresponding to the human gene responsible for Batten's disease, is not essential for viability, mitochondrial function, or degradation of mitochondrial ATP synthase. Yeast 13:691-697. https://doi.org/10.1002/(SICI)1097-0061(19970630)13:8<691::AID-YEA123>3.0.CO;2-D
  54. Persaud-Sawin DA, McNamara JO, 2nd, Rylova S, Vandongen A, Boustany RM (2004) A galactosylceramide binding domain is involved in trafficking of CLN3 from Golgi to rafts via recycling endosomes. Pediatr Res 56:449-463. https://doi.org/10.1203/01.PDR.0000136152.54638.95
  55. Phillips SN, Benedict JW, Weimer JM, Pearce DA (2005) CLN3, the protein associated with batten disease: structure, function and localization. J Neurosci Res 79:573-583. https://doi.org/10.1002/jnr.20367
  56. Pierret C, Morrison JA, Kirk MD (2008) Treatment of lysosomal storage disorders: focus on the neuronal ceroidlipofuscinoses. Acta Neurobiol Exp (Wars) 68:429-442.
  57. Pohl S, Mitchison HM, Kohlschutter A, van Diggelen O, Braulke T, Storch S (2007) Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue. J Neurochem 103:2177-2188. https://doi.org/10.1111/j.1471-4159.2007.04920.x
  58. Qiao X, Lu JY, Hofinann SL (2007) Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response. BMC Neurosci 8:95. https://doi.org/10.1186/1471-2202-8-95
  59. Rakheja D, Narayan SB, Bennett MJ (2008) The function of CLN3P, the Batten disease protein. Mol Genet Metab 93:269-274. https://doi.org/10.1016/j.ymgme.2008.01.001
  60. Rakheja D, Narayan SB, Pastor N, Bennett MJ (2004) CLN3P, the Batten disease protein, localizes to membrane lipid rafts (detergent-resistant membranes). Biochem Biophys Res Commun 317:988-991. https://doi.org/10.1016/j.bbrc.2004.03.146
  61. Ranta S, Topcu M, Tegelberg S, Tan H, Ustubutun A, Saatci I, Dutke A, Enders H, Pohl K, Alembik Y and others (2004) Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. Hum Mutat 23:300-305. https://doi.org/10.1002/humu.20018
  62. Robertson T, Tannenberg AE, Hiu J, Reimers J (2008) 53-year-old man with rapid cognitive decline. Brain Pathol 18:292-294. https://doi.org/10.1111/j.1750-3639.2008.00160.x
  63. Salonen T, Heinonen-Kopra O, Vesa J, Jalanko A (2001) Neuronal trafficking of palmitoyl protein thioesterase provides an excellent model to study the effects of different mutations which cause infantile neuronal ceroid lipofuscinocis. Mol Cell Neurosci 18:131-140. https://doi.org/10.1006/mcne.2001.1010
  64. Salonen T, Jarvela I, Peltonen L, Jalanko A (2000) Detection of eight novel palmitoyl protein thioesterase (PPT) mutations underlying infantile neuronal ceroid lipofuscinosis (INCL;CLN1). Hum Mutat 15:273-279. https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<273::AID-HUMU8>3.0.CO;2-L
  65. Santavuori P, Lauronen L, Kirveskari E, Aberg L, Sainio K, Autti T (2000) Neuronal ceroid lipofuscinoses in childhood. Neurol Sci 21:S35-S41. https://doi.org/10.1007/s100720070038
  66. Schulz A, Dhar S, Rylova S, Dbaibo G, Alroy J, Hagel C, Artacho I, Kohlschutter A, Lin S, Boustany RM (2004) Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant. Ann Neurol 56:342-350. https://doi.org/10.1002/ana.20187
  67. Schulz A, Mousallem T, Venkataramani M, Persaud-Sawin DA, Zucker A, Luberto C, Bielawska A, Bielawski J, Holthuis JC, Jazwinski SM and others (2006) The CLN9 protein, a regulator of dihydrocerarnide synthase. J BioI Chem 281:2784-2794. https://doi.org/10.1074/jbc.M509483200
  68. Siintola E, Topcu M, Kohlschutter A, Salonen T, Joensuu T, Anttonen AK, Lehesjoki AE (2005) Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin. Clin Genet 68:167-173. https://doi.org/10.1111/j.1399-0004.2005.00471.x
  69. Sleat DE, EI-Banna M, Sohar I, Kim KH, Dobrenis K, Walkley SU, Lobel P (2008) Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis. Mol Genet Metab 94:222-233. https://doi.org/10.1016/j.ymgme.2008.01.014
  70. Stogmann E, El Tawil S, Wagenstaller J, Gaber A, Edris S, Abdelhady A, Assem-Hilger E, Leutmezer F, Bonelli S, Baumgartner C and others (2009) A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. Neurogenetics 10:73-77. https://doi.org/10.1007/s10048-008-0153-1
  71. Taschner PE, de Vos N, Breuning MH (1997) Cross-species homology of the CLN3 gene. Neuropediatrics 28:18-20. https://doi.org/10.1055/s-2007-973658
  72. Terry JL, Rose-Mary NB, John WA, Kenneth LD, Karenschlumpf, Alan JB, James F, Gusella & Jonathan H (1995) Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell 82:949-957. https://doi.org/10.1016/0092-8674(95)90274-0
  73. Topcu M, Tan H, Yalnizoglu D, Usubutun A, Saatci I, Aynaci M, Anlar B, Topaloglu H, Turanli G, Kose G and others (2004) Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk J Pediatr 46:1-10.
  74. Vadlamudi L, Westmoreland BF, Klass DW, Parisi JE (2003) Electroencephalographic findings in Kufs disease. Clin Neurophysiol 114:1738-1743. https://doi.org/10.1016/S1388-2457(03)00111-1
  75. Varilo T, Savukoski M, Norio R., Santavuori P, Peltonen L, Jarvela I (1996) The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. Am J Hum Genet 58:506-512.
  76. 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. https://doi.org/10.1093/hmg/ddm324
  77. Wisniewski KE, Kida E, Golabek AA, Kaczmarski W, Connell F, Zhong N (2001) Neuronal ceroid lipofuscinoses: classification and diagnosis. Adv Genet 45:1-34. https://doi.org/10.1016/S0065-2660(01)45002-4
  78. Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB (2001) Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med 7:478-784. https://doi.org/10.1038/86554
  79. Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Saha A, Wei H, Xu Y, Xiao YJ, Zhang P and others (2007) Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. Hum Mol Genet 16:837-847. https://doi.org/10.1093/hmg/ddm029
  80. Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB (2006) Pahnitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum Mol Genet 15:337-346. https://doi.org/10.1093/hmg/ddi451