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Mechanisms of neurodegeneration in neuronal ceroid-lipofuscinoses

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Abstract

Neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative diseases and autosomal recessive lysosomal storage disorders. We examined the involvement of cell death, oxidative stress, and glutamate excitotoxicity using immunohistochemistry against Bcl-2, Bcl-x, oxidative products to proteins, lipids and DNA, calcium-binding proteins (calbindin-D28K, parvalbumin, calretinin), and glial glutamate transporters (excitatory amino acid transporters 1 and 2), in addition to terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) in the brains from three cases of late infantile form of NCL (LINCL) and one case of juvenile form of NCL (JNCL) to investigate the neurodegenerative mechanisms. In the cerebral and cerebellar cortex, all of three LINCL cases demonstrated neurons with TUNEL-immunoreactive nuclei, whereas the JNCL case did not show TUNEL-immunoreactive nuclei. The coexistence of the nuclear TUNEL-immunoreactivity nuclei and cytoplasmic deposition of 4-hydroxy-2-nonenal-modified protein in the frontal cortex and hypoglossal nucleus may suggest a possible interrelationship between DNA fragmentation and lipid oxidation in LINCL. Additionally, glycoxidation of protein and oxidative stress to DNA seemed to be involved in the cerebellar and cerebral degeneration, respectively. Interneurons immunoreactive for calbindin-D28K and parvalbumin were severely reduced in the cerebral cortex, whereas those for calretinin were comparatively well preserved in LINCL, indicating the possibility of altered GABAergic system. The disturbance of expression of glial glutamate transporters seemed to be heterogeneous and mild. These findings suggest the possibility of new treatments for neurodegeneration in LINCL using antioxidative agents and/or GABAergic medications.

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References

  1. Beasley CL, Zhang ZJ, Patten I, Reynolds GP (2002) Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Soc Biol Psychiatry 52:708–715

    Article  CAS  Google Scholar 

  2. Ben-Manachem E, Kyllerman M, Marklund S (2000) Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res 40:33–39

    Article  PubMed  Google Scholar 

  3. Emerit J, Edeas M, Bricarie F (2004) Neurodegenerative diseases and oxidative stress. Biomed Phamacother 58:39–46

    Article  CAS  Google Scholar 

  4. Ezaki J, Kominami E (2004) The intracellular location and function of proteins of neuronal ceroid lipofuscinoses. Brain Pathol 14:77–85

    Article  PubMed  CAS  Google Scholar 

  5. Goebel HH, Wisniewski KE (2004) Current state of clinical and morphological features in human NCL. Brain Pathol 14:61–69

    Article  PubMed  CAS  Google Scholar 

  6. Haltia M (2003) The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 62:1–13

    PubMed  Google Scholar 

  7. Hayashi M (2001) Neuropathology of the limbic system and brainstem in West syndrome. Brain Dev 23:516–522

    Article  PubMed  CAS  Google Scholar 

  8. Hayashi M, Arai N, Murakami T, Morimatsu Y, Oda M, Matsuyama H (1998) A study of cell death in Werdnig Hoffmann disease brain. Neurosci Lett 243:117–120

    Article  PubMed  CAS  Google Scholar 

  9. Hayashi M, Itoh M, Araki S, Kumada S, Shioda K, Tamagawa K, Mizutani T, Morimatsu Y, Minagwa M, Oda M (2001) Oxidative stress and glutamate transport in hereditary nucleotide repair disorders. J Neuropathol Exp Neurol 60:350–356

    PubMed  CAS  Google Scholar 

  10. Hayashi M, Arai N, Satoh J, Suzuki H, Katayama K, Tamagawa K, Morimatsu Y (2002) Neurodegenerative mechanisms in subacute sclerosing panencephalitis. J Child Neurol 17:725–730

    PubMed  Google Scholar 

  11. Hayashi M, Araki S, Arai N, Kumada S, Itoh M, Tamagawa K, Oda M, Morimatsu Y (2002) Oxidative stress and disturbed glutamate transport in spinal muscular atrophy. Brain Dev 24:770–775

    Article  PubMed  Google Scholar 

  12. Hayashi M, Araki S, Kohyama J, Shioda K, Futamatsu R, Tamagawa K (2004) Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. J Neuropathol Exp Neurol 63:1048–1057

    PubMed  Google Scholar 

  13. Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R (2005) Oxidative nucleotide damage and superoxide dismutase expression in the brains of xeroderma pigmentosum group A and Cockayne syndrome. Brain Dev 27:34–38

    Article  PubMed  Google Scholar 

  14. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53:S26–S38

    Article  PubMed  CAS  Google Scholar 

  15. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, Makita Z, Sasaki N, Tashiro K (2003) Glycation—a sweet tempter for neuronal death. Brain Res Brain Res Rev 41:306–323

    Article  PubMed  CAS  Google Scholar 

  16. Kumada S, Hayashi M, Mizuguchi M, Nakano I, Morimatsu Y, Oda M (2000) Cerebellar degeneration in hereditary dentatorubral-pallidoluysian atrophy and Machado–Joseph disease. Acta Neuropathol 99:48–54

    Article  PubMed  CAS  Google Scholar 

  17. Kurata K, Hayashi M, Satoh J, Kojima H, Nagata J, Tamagawa K, Shinohara T, Morimatsu Y, Kominami E (1999) Pathological study on sibling autopsy cases of the late infantile form of neuronal ceroid lipofuscinosis. Brain Dev 21:63–67

    Article  PubMed  CAS  Google Scholar 

  18. Lake BD, Hall NA (1993) Immunolocalization studies of subunit c in late infantile and juvenile Batten disease. J Inherit Metab Dis 16:263–266

    Article  PubMed  CAS  Google Scholar 

  19. Lane SC, Jolly RD, Schmechel DE, Alroy J, Boustany RM (1996) Apoptosis as the mechanism of neurodegeneration in Batten’s disease. J Neurochem 67:677–683

    Article  PubMed  CAS  Google Scholar 

  20. Liu W, Kato M, Akhand AA, Hayakawa A, Suzuki H, Miyata T, Kurokawa K, Hotta Y, Ishikawa N, Nakashima I (2000) 4-hydroxynonenal induces a cellar redox status-related activation of the caspase cascade for apoptotic cell death. J Cell Sci 113:635–641

    PubMed  CAS  Google Scholar 

  21. Mathern GW, Mendoza BS, Lozada BS, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L, Born DE, Sakamoto AC, Assirati JA, Fried I, Peacock WJ, Ojemann GA, Adelson PD (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472

    PubMed  CAS  Google Scholar 

  22. Mikkonen M, Alafuzoff I, Tapiola T, Soininen H, Miettinen R (1999) Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin-D28 immunoreactivity in the entorhinal cortex in Alzheimer’s disease. Neuroscience 92:515–532

    Article  PubMed  CAS  Google Scholar 

  23. Mitchison HM, Lim MJ, Cooper JD (2004) Selectivity and types of cell death in the neuronal ceroid lipofuscinoses. Brain Pathol 14:86–96

    Article  PubMed  CAS  Google Scholar 

  24. Mole SE (2004) The genetic spectrum of human neuronal ceroid-lipofuscinoses. Brain Pathol 14:70–76

    Article  PubMed  CAS  Google Scholar 

  25. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    PubMed  CAS  Google Scholar 

  26. Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, de Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43

    Article  PubMed  CAS  Google Scholar 

  27. Puranam KL, Guo WX, Qian WH, Nikbakht K, Boustany RM (1999) CLN3 defines a novel antiapoptotic pathway operative in neurodegeneration and mediated by ceramide. Mol Genet Metab 66:294–308

    Article  PubMed  CAS  Google Scholar 

  28. Sharp JD, Wheeler RB, Lake BD, Savukoski M, Jarvela IE, Peltonen L, Gardiner RM, Williams RE (1997) Loci for classical and a variant late infantile neuronal ceroid lipofuscinoses map to chromosomes 11p15 and 15q21–23. Hum Mol Genet 6:591–595

    Article  PubMed  CAS  Google Scholar 

  29. Sleat DE, Donnelly RJ, Lackland H, Liu CG, Sohar I, Pullarkat RK, Lobel P (1997) Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid-lipofuscinosis. Science 277:1802–1805

    Article  PubMed  CAS  Google Scholar 

  30. Takedo A, Yasuda T, Miyata T, Mizuno K, Li M, Yoneyama S, Horie K, Maeda K, Sobue G (1996) Immunohistochemical study of advanced glycation end products in aging and Alzheimer’s disease brain. Neurosci Lett 221:17–20

    Article  PubMed  CAS  Google Scholar 

  31. The International Batten Disease Consortium (1995) Isolation of a novel gene underlying Batten disease, CLN3. Cell 82:949–957

    Article  Google Scholar 

  32. Toyokuni S (1999) Reactive oxygen species-induced molecular damage and its application in pathology. Pathol Int 49:91–102

    Article  PubMed  CAS  Google Scholar 

  33. Tyynelä J, Cooper JD, Khan MN, Shemilts SJ, Haltia M (2004) Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation. Brain Pathol 14:349–357

    Article  PubMed  Google Scholar 

  34. Walkley SU (1998) Cellular pathology of the lysosomal strage disorders. Brain Pathol 8:175–193

    Article  PubMed  CAS  Google Scholar 

  35. Zarkovic K (2003) 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24:293–303

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Metropolitan Fuchu Medical Center for SMID, 2-9-2 Musashi-dai, Fuchu-shi, 183-0042, Tokyo, Japan

    Yasuo Hachiya, Akira Uchiyama & Kiyoko Kurata

  2. Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

    Masaharu Hayashi

  3. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Satoko Kumada

  4. Department of Laboratory Medicine, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan

    Kuniaki Tsuchiya

Authors
  1. Yasuo Hachiya
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  2. Masaharu Hayashi
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  3. Satoko Kumada
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  4. Akira Uchiyama
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  5. Kuniaki Tsuchiya
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  6. Kiyoko Kurata
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Correspondence to Yasuo Hachiya.

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Hachiya, Y., Hayashi, M., Kumada, S. et al. Mechanisms of neurodegeneration in neuronal ceroid-lipofuscinoses. Acta Neuropathol 111, 168–177 (2006). https://doi.org/10.1007/s00401-005-0024-x

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  • DOI: https://doi.org/10.1007/s00401-005-0024-x

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