Skip to main content

Neuronale Zeroidlipofuszinosen (NCL) im Tiermodell

NCL in animal models

Der Ophthalmologe volume 107, pages 621–627 (2010)Cite this article

Zusammenfassung

Neuronale Zeroidlipofuszinosen (NCL) sind schwer verlaufende und zum vorzeitigen Tod führende neurodegenerative Erkrankungen. Sie gehören zu der Gruppe der lysosomalen Speichererkrankungen. Epileptische Anfälle, Demenz und motorische Defizite sind häufige Symptome, die vor dem gänzlichen Persönlichkeitsabbau und Tod anzutreffen sind. Man unterscheidet zurzeit 10 Unterformen; bei 8 Varianten ist die genetische Grundlage bekannt. Bei den involvierten Proteinen handelt es sich um zytoplasmatische oder Membranproteine, deren Funktion jedoch in den meisten Fällen noch unklar ist. Die Erforschung der Pathologie und Pathophysiologie der NCL ist in hohem Maße von Tiermodellen abhängig, wobei Mausmodelle, die es für alle Unterformen mit bekanntem Gendefekt gibt, eine herausragende Rolle spielen. Leider ist der retinale Phänotyp bei einigen Mausmodellen nicht so ausgeprägt wie beim Menschen, was die Beurteilung eines positiven Therapieeffekts erschwert. Aufgrund des Schweregrads der NCL werden schon heute lediglich im Mausmodell untersuchte Therapiestrategien beim Menschen angewendet.

Abstract

Neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative diseases leading to early death. They belong to the group of lysosomal storage diseases. Epileptic seizures, dementia and motor deficits are frequent symptoms which are to be found prior to a total dismantling of personality and death. At present 10 subtypes of NCL can be distinguished from which the genetic defect is known in eight. The encoded proteins are soluble or membrane proteins whose function is still unclear in most cases. The investigation of the pathology and pathophysiology of NCL is highly dependent on animal models. Mouse models existing for all forms with a known genetic defect play a prominent role. Unfortunately, the retinal phenotype of some mouse models is milder than in humans rendering the appreciation of a positive therapeutic effect more difficult. Because of the severity of NCL, therapy strategies only established in a mouse model will be transferred to humans very quickly.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Abb. 1
Abb. 2

Literatur

  1. Awano T, Katz ML, O’Brien DP et al (2006a) A mutation in the cathepsin D gene (CTSD) in American bulldogs with neuronal ceroid lipofuscinosis. Mol Genet Metab 87:341–348

    Article  CAS  PubMed  Google Scholar 

  2. Awano T, Katz ML, O’Brien DP et al (2006b) A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab 89:254–260

    Article  CAS  PubMed  Google Scholar 

  3. Bertamini M, Marzani B, Guarneri R et al (2002) Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system. Eur J Neurosci 16:2291–2296

    Article  CAS  PubMed  Google Scholar 

  4. Cho S, Dawson PE, Dawson (2000) Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells. J Neurosci Res 62:234–234

    Article  CAS  PubMed  Google Scholar 

  5. Cotman SL, Vrbanac V, Lebel LA et al (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

    Article  CAS  PubMed  Google Scholar 

  6. Das AK, Becerra CH, Yi W et al (1998) Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest 102:361–370

    Article  CAS  PubMed  Google Scholar 

  7. Voer G de, Bent P van der, Rodrigues AJ et al (2005) Deletion of the caenorhabditis elegans homologues of the CLN3 gene, involved in human juvenile neuronal ceroid lipofuscinosis, causes a mild progeric phenotype. J Inherit Metab Dis 28:1065–1080

    Article  CAS  PubMed  Google Scholar 

  8. Eliason SL, Stein CS, Mao Q et al (2007) A knock-in reporter model of Batten disease. J Neurosci 27:9826–9834

    Article  CAS  PubMed  Google Scholar 

  9. Elshatory Y, Brooks AI, Chattopadhyay S (2003) Early changes in gene expression in two models of Batten disease. FEBS Lett 538:207–212

    Article  CAS  PubMed  Google Scholar 

  10. Frugier T, Mitchell NL, Tammen I et al (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

    Article  CAS  PubMed  Google Scholar 

  11. Griffey M, Macauley SL, Ogilvie JM, Sands MS (2005) AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. Mol Ther 12:413–421

    Article  CAS  PubMed  Google Scholar 

  12. Griffey MA, Wozniak D, Wong M et al (2006) CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol Ther 13:538–547

    Article  CAS  PubMed  Google Scholar 

  13. Gupta P, Soyombo AA, Atashband A et al (2001) Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proc Natl Acad Sci U S A 98:13566–135671

    Article  CAS  PubMed  Google Scholar 

  14. Houweling PJ, Cavanagh JA, Palmer DN et al (2006) Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. Biochim Biophys Acta 1762:890–897

    CAS  PubMed  Google Scholar 

  15. Jalanko A, Vesa J, Manninen T et al (2005) Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiol Dis 18:226–241

    Article  CAS  PubMed  Google Scholar 

  16. J Jalanko A, Braulke T (2009) Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 1793:697–709

    Article  Google Scholar 

  17. Jolly RD, Shimada A, Dopfmer I et al (1989) Ceroid-lipofuscinosis (Batten’s disease): pathogenesis and sequential neuropathological changes in the ovine model. Neuropathol Appl Neurobiol 15:371–383

    Article  CAS  PubMed  Google Scholar 

  18. Katz ML, Shibuya H, Liu PC et al (1999) A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease). J Neurosci Res 57:551–556

    Article  CAS  PubMed  Google Scholar 

  19. Katz ML, Khan S, Awano T et al (2005) A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541–547

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  PubMed  Google Scholar 

  21. Koike M, Nakanishi H, Saftig P et al (2000) Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci 20:6898–6906

    CAS  PubMed  Google Scholar 

  22. Koike M, Shibata M, Ohsawa Y et al (2003) Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice. Mol Cell Neurosci 22:146–161

    Article  CAS  PubMed  Google Scholar 

  23. Kopra O, Vesa J, Schantz C von et al (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

    Article  CAS  PubMed  Google Scholar 

  24. Lang AH, Hirvasniemi A, Siivola J (1997) Neurophysiological findings in the northern epilepsy syndrome. Acta Neurol Scand 95:1–8

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. Melville SA, Wilson CL, Chiang CS et al (2005) A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in border collie dogs. Genomics 86:287–294

    Article  CAS  PubMed  Google Scholar 

  27. Messer A, Plummer J, MacMillen MC, Frankel WN (1995) Genetics of primary and timing effects in the mnd mouse. Am J Med Genet 57:361–364

    Article  CAS  PubMed  Google Scholar 

  28. Mitchison HM, Bernard DJ, Greene ND et al (1999) Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten mouse model consortium. Neurobiol Dis 6:321–334. Erratum in. Neurobiol Dis 2000 7(2):127

    Article  Google Scholar 

  29. Partanen S, Haapanen A, Kielar C et al (2008) Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol 67:16–29

    Article  CAS  PubMed  Google Scholar 

  30. Passini MA, Dodge JC, Bu J et al (2006) Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J Neurosci 26:1334–1342

    Article  CAS  PubMed  Google Scholar 

  31. Ranta S, Zhang Y, Ross B et al (1999) The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet 23:233–236

    Article  CAS  PubMed  Google Scholar 

  32. Saftig P, Hetman M, Schmahl W et al (1995) Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 14:3599–3608

    CAS  PubMed  Google Scholar 

  33. Schantz C, Kielar C, Hansen SN et al (2009) Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL. Neurobiol Dis 34:308–319

    Article  Google Scholar 

  34. Schulz A, Mousallem T, Venkataramani M et al (2006) The CLN9 protein, a regulator of dihydroceramide synthase. J Biol Chem 281:2784–2794

    Article  CAS  PubMed  Google Scholar 

  35. Seigel GM, Lotery A, Kummer A et al (2002) Retinal pathology and function in a Cln3 knockout mouse model of juvenile neuronal ceroid Lipofuscinosis (Batten disease). Mol Cell Neurosci 19:515–527

    Article  CAS  PubMed  Google Scholar 

  36. Seigel GM, Wagner J, Wronska A et al (2005) Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis. Eye (Lond) 19:1306–1312

    Google Scholar 

  37. Siintola E, Partanen S, Strömme P et al (2006) Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129:1438–1445

    Article  PubMed  Google Scholar 

  38. Sleat DE, Wiseman JA, El-Banna M et al (2004) A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. J Neurosci 24:9117–9126

    Article  CAS  PubMed  Google Scholar 

  39. Sondhi D, Hackett NR, Peterson DA et al (2007) Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Ther 15:481–491

    Article  CAS  PubMed  Google Scholar 

  40. Steinfeld R, Reinhardt K, Schreiber K et al (2006) Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 78:988–998

    Article  CAS  PubMed  Google Scholar 

  41. Tyynelä J, Sohar I, Sleat DE et al (2000) A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J 19:2786–2792

    Article  PubMed  Google Scholar 

  42. Weimer JM, Custer AW, Benedict JW et al (2006) Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons. Neurobiol Dis 22:284–293

    Article  PubMed  Google Scholar 

  43. Wheeler RB, Sharp JD, Schultz RA et al (2002) The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet 70:537–542

    Article  CAS  PubMed  Google Scholar 

  44. Worgall S, Sondhi D, Hackett NR et al (2008) Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 19:463–474

    Article  CAS  PubMed  Google Scholar 

  45. Zelnik N, Mahajna M, Iancu TC et al (2007) A novel mutation of the CLN8 gene: is there a mediterranean phenotype? Pediatr Neurol 36:411–413

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Keine Angaben.

Author information

Affiliations

  1. Arbeitsbereich Strabologie/Neuroophthalmologie, Augenklinik, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Deutschland

    K. Rüther

Authors
  1. K. Rüther
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Rüther.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rüther, K. Neuronale Zeroidlipofuszinosen (NCL) im Tiermodell. Ophthalmologe 107, 621–627 (2010). https://doi.org/10.1007/s00347-009-2108-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00347-009-2108-9

Schlüsselwörter

  • Neuronale Zeroidlipofuszinose
  • NCL
  • Tiermodell
  • Mausmodell
  • Netzhautdegeneration

Keywords

  • Neuronal ceroid lipofuscinoses
  • NCL
  • Animal models
  • Mouse models
  • Retinal degeneration