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근위축측삭경화증과 전두측두엽치매에서 TAR DNA Binding Protein (TDP-43)의 병인론적 역할

The Pathogenetic Role of TAR DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

강사윤
대한신경과학회 (Korean Neurological Association)|2011.02|대한신경과학회지 (Journal of the Korean Neurological Association)|제29권 제1호|pp. 1-8

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참고문헌

키워드

Amyotrophic lateral sclerosisNeurodegenerationFrontotemporal lobar degenerationTAR DNA binding protein-43 (TDP-43)
주제분류신경과학

초록

The recent identification of the transactive response DNA binding protein with a molecular weight of 43 kDa (TDP-43) as the major pathological protein, in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), provides the new insight into understanding disease processes. The pathogenesis of both diseases is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. The number of degenerative diseases associated with TDP-43 has increased, leading to the new designation "TDP-43 proteinopathy". TDP-43 is a highly conserved protein ubiquitously expressed in many tissues including the central nervous system where it is present in neuronal and glial nuclei and to a lesser extent in the cytoplasm. Currently, TDP-43 has been implicated in regulating gene transcription and alternative splicing, in addition to maintaining mRNA stability. However, we still need to investigate the effects of posttranslational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage, on its regulation of various cellular processes. We review recently published studies of TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders and both ALS and FTLD-U are closely related conditions linked to similar mechanism of neurodegeneration.

Abstract

The recent identification of the transactive response DNA binding protein with a molecular weight of 43 kDa (TDP-43) as the major pathological protein, in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), provides the new insight into understanding disease processes. The pathogenesis of both diseases is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. The number of degenerative diseases associated with TDP-43 has increased, leading to the new designation "TDP-43 proteinopathy". TDP-43 is a highly conserved protein ubiquitously expressed in many tissues including the central nervous system where it is present in neuronal and glial nuclei and to a lesser extent in the cytoplasm. Currently, TDP-43 has been implicated in regulating gene transcription and alternative splicing, in addition to maintaining mRNA stability. However, we still need to investigate the effects of posttranslational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage, on its regulation of various cellular processes. We review recently published studies of TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders and both ALS and FTLD-U are closely related conditions linked to similar mechanism of neurodegeneration.

참고문헌 (60)

  1. Mackenzie IR, "Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum", J Neuropathol Exp Neurol, 64, pp.730~739 (2005)
  2. Lomen-Hoerth C, "The overlap of amyotrohic lateral sclerosis and frontotemporal dementia", Neurology, 59, pp.1077~1079 (2002)
  3. McKhann GM, "Clinical and pathological diagnosis of frontotemporal dementia: report of the work group on frontotemporal dementia and Pick’s disease", Arch Neurol, 58, pp.1803~1809 (2001)
  4. Ratnavalli E, "The prevalence of frontotemporal dementia", Neurology, 58, pp.1615~1621 (2002)
  5. Forman MS, "Frontotemporal dementia: clinicopathological correlations", Ann Neurol, 59, pp.952~962 (2006)
  6. Leigh PN, "Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis", Morphology, distribution, and specificity. Brain, 114, pp.775~788 (1991)
  7. Arai T, "TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis", Biochem Biophys Res Commun, 351, pp.602~611 (2006)
  8. Neumann M, "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis", Science, 314, pp.130~133 (2006)
  9. Geser F, "Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases", J Neurol, 256, pp.1205~1214 (2009)
  10. Kwiakowski TJ Jr, "Mutations in the FUS", TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis, 2009, pp.323, 1205~1208
  11. Vance C, "Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6", Science, 323, pp.1208~1211 (2009)
  12. Mackenzie IR, "Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update", Acta Neuropathol, 119, pp.1~4 (2010)
  13. Mackenzie IR, "TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia", Lancet Neurol, 9, pp.995~1007 (2010)
  14. Chen-Plotkin AS, "TAR DNA-binding protein 43 in neurodegenerative disease", Nat Rev Neurol, 6, pp.211~220 (2010)
  15. Mackenzie IR, "The role of TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia", Curr Opin Neurol, 21, pp.693~700 (2008)
  16. Ou SH, "Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs", J Virol, 69, pp.3584~3596 (1995)
  17. Ayala YM, "TDP 43 depletion rescues aberrant CFTR exon 9 skipping", FEBS Lett, 580, pp.1339~1344 (2006)
  18. Mercado PA, "Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene", Nucleic Acids Res, 33, pp.6000~6010 (2005)
  19. Wang HY, "Structural diversity and functional implications of the eukaryotic TDP gene family", Genomics, 83, pp.130~139 (2004)
  20. Buratti E, "Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9", J Biol Chem, 276, pp.36337~36343 (2001)
  21. Strong MJ, "TDP43 is a human low molecular weight neurofilament (HNFL) MRNA-binding protein", Mol Cell Neurosci, 35, pp.320~327 (2007)
  22. Winton MJ, "Disturbance of nuclear and cytoplasmic Tar DNA binding protein (TDP-43) induces disease-like redistribution, sequestration and aggregate formation", J Biol Chem, 283, pp.13302~13309 (2008)
  23. Cook C, "TDP-43 in neurodegenerative disorders", Expert Opin Biol Ther, 8, pp.969~978 (2008)
  24. Buratti E, "TDP-43 binds heterogeneous nuclear ribonucleoprotein A", B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing, 2005, pp.280, 37572~37584
  25. Baker M, "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17", Nature, 442, pp.916~919 (2006)
  26. Cruts M, "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21", Nature, 442, pp.920~924 (2006)
  27. Davidson Y, "Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43", Acta Neuropathol, 113, pp.521~533 (2007)
  28. Cairns NJ, "TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions", Am J Pathol, 171, pp.227~240 (2007)
  29. Geser F, "Clinical and pathological continuum of multisystem TDP-43 proteinopathies", Arch Neurol, 66, pp.180~189 (2009)
  30. Josephs KA, "Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes", Acta Neuropathol, 118, pp.349~358 (2009)
  31. Mackenzie IR, "Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype", Acta Neuropathol, 112, pp.539~549 (2006)
  32. Newmann M, "TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations", J Neuropathol Exp Neurol, 66, pp.152~157 (2007)
  33. Josephs KA, "Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations", J Neuropathol Exp Neurol, 66, pp.142~151 (2007)
  34. Lomen-Hoerth C, "Are amyotrophic lateral sclerosis patients cognitively normal", Neurology, 60, pp.1094~1097 (2003)
  35. Strong MJ, "Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis", Amyotroph Lateral Scler, 10, pp.131~146 (2009)
  36. Tan CF, "TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation", Acta Neuropathol, 113, pp.535~542 (2007)
  37. Mackenzie IR, "Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations", Ann Neurol, 61, pp.427~434 (2007)
  38. Higashi S, "TDP-43 physically interacts with amyotrophic lateral sclerosis-linked mutant CuZn superoxide dismutase", Neurochem Int, 57, pp.906~913 (2010)
  39. Bodansky A, "TDP-43 and ubiquitinated cytoplasmic aggregates in sporadic ALS are low frequency and widely distributed in the lower motor neuron columns independent of disease spread", Amyotroph Lateral Scler, 11, pp.321~327 (2010)
  40. Geser F, "Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis", Arch Neurol, 65, pp.636~641 (2008)
  41. Dickson DW, "TDP-43 in differential diagnosis of motor neuron disorders", Acta Neuropathol, 114, pp.71~79 (2007)
  42. Pamphlett R, "TDP-43 neuropathology is similar in sporadic amyotrophic lateral sclerosis with or without TDP-43 mutations", Neuropathol Appl Neurobiol, 35, pp.222~225 (2009)
  43. Van Deerlin VM, "TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis", Lancet Neurol, 7, pp.409~416 (2008)
  44. Watts GD, "Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin- containing protein", Nat Genet, 36, pp.377~381 (2004)
  45. Wider C, "Pallidonigral TDP-43 pathology in Perry syndrome", Parkinsonism Relat Disord, 15, pp.281~286 (2009)
  46. Kabashi E, "Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficit in vivo", Hum Mol Genet, 19, pp.671~683 (2010)
  47. Feiguin F, "Depletion of TDP-43 affects Drosophila motor neurons terminal synapsis and locomotive behavior", FEBS Lett, 583, pp.1586~1592 (2009)
  48. Johnson BS, "A yeast TDP-43 proteinopathy model: exploring the molecular determinants of TDP-43 aggregation and cellular toxicity", Proc Natl Acad Sci U S A, 105, pp.6439~6444 (2008)
  49. Arai T, "Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy", Neuropathology, 30, pp.170~181 (2010)
  50. Wegorzewska I, "TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration", Proc Natl Acad Sci U S A, 106, pp.18809~18814 (2009)
  51. Kabashi E, "TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis", Nat Genet, 40, pp.572~574 (2008)
  52. Sreedharan J, "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis", Science, 319, pp.1668~1672 (2008)
  53. Daoud H, "Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis", J Med Genet, 46, pp.112~114 (2009)
  54. Kirby J, "Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis", Neurogenetics, 11, pp.217~225 (2010)
  55. Finch N, "Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members", Brain, 132, pp.583~591 (2009)
  56. Kelley BJ, "Prominent phenotypic variability associated with mutations in progranulin", Neurobiol Aging, 30, pp.739~751 (2009)
  57. Benajiba L, "TARDBP mutations in motoneuron disease with Frontotemporal lobar degeneration", Ann Neurol, 65, pp.470~473 (2009)
  58. Forman MS, "TDP-43: a novel neurodege nerative proteinopathy", Curr Opin Neurobiol, 17, pp.548~555 (2007)
  59. Steinacker P, "TDP-43 in cerebrospinal fluid of patients with Frontotemporal lobar degeneration and amyotrophic lateral sclerosis", Arch Neurol, 65, pp.1481~1487 (2008)
  60. Kasai T, "Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis", Acta Neuropathol, 117, pp.55~62 (2009)

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