Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.

[1]  William T. Hu,et al.  Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease , 2008, Acta Neuropathologica.

[2]  P. Lantos,et al.  Overlap between neurodegenerative disorders , 2005, Neuropathology : official journal of the Japanese Society of Neuropathology.

[3]  M. Farrer,et al.  DCTN1 mutations in Perry syndrome , 2009, Nature Genetics.

[4]  I. Mackenzie,et al.  The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia , 2008, Current opinion in neurology.

[5]  D. Drubach Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions , 2009 .

[6]  Tom Misteli,et al.  TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression , 2008, Proceedings of the National Academy of Sciences.

[7]  J. Trojanowski,et al.  Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations , 2008, Acta Neuropathologica.

[8]  T. Dörk,et al.  Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping , 2001, The EMBO journal.

[9]  H. Arai,et al.  Appearance pattern of TDP-43 in Japanese frontotemporal lobar degeneration with ubiquitin-positive inclusions , 2007, Neuroscience Letters.

[10]  M. Grossman,et al.  Motor Neuron Disease and Frontotemporal Lobar Degeneration: A Tale of Two Disorders Linked To TDP-43 , 2007, Neurosignals.

[11]  I-Fan Wang,et al.  TDP-43 Overexpression Enhances Exon 7 Inclusion during the Survival of Motor Neuron Pre-mRNA Splicing* , 2008, Journal of Biological Chemistry.

[12]  I. Mackenzie,et al.  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 , 2005, Journal of neuropathology and experimental neurology.

[13]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[14]  D Harrich,et al.  Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs , 1995, Journal of virology.

[15]  J. Trojanowski,et al.  Concomitant TAR-DNA-Binding Protein 43 Pathology Is Present in Alzheimer Disease and Corticobasal Degeneration but Not in Other Tauopathies , 2008, Journal of neuropathology and experimental neurology.

[16]  J. Trojanowski,et al.  Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. , 2008, Human molecular genetics.

[17]  N. Cairns,et al.  Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy , 2008, Journal of Neural Transmission.

[18]  Murray Grossman,et al.  TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions. , 2007, Archives of neurology.

[19]  B. Brownell,et al.  The central nervous system in motor neurone disease , 1970, Journal of neurology, neurosurgery, and psychiatry.

[20]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[21]  T. Paunesku,et al.  Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions , 2007, Acta Neuropathologica.

[22]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[23]  J. Trojanowski,et al.  Amyotrophic lateral sclerosis-plus syndrome with TAR DNA-binding protein-43 pathology. , 2009, Archives of neurology.

[24]  E. Buratti,et al.  Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene , 2005, Nucleic acids research.

[25]  Hurng‐Yi Wang,et al.  Structural diversity and functional implications of the eukaryotic TDP gene family. , 2004, Genomics.

[26]  J. Morris,et al.  TDP‐43 A315T mutation in familial motor neuron disease , 2008, Annals of neurology.

[27]  John L. Robinson,et al.  Clinical and pathological continuum of multisystem TDP-43 proteinopathies. , 2009, Archives of neurology.

[28]  D. Neary,et al.  TDP-43 gene analysis in frontotemporal lobar degeneration , 2007, Neuroscience Letters.

[29]  M. Morita,et al.  Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis , 2008, Annals of neurology.

[30]  H. Akiyama,et al.  Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies , 2009, Acta Neuropathologica.

[31]  T. Beach,et al.  Abnormal phosphorylation of Ser409/410 of TDP‐43 in FTLD‐U and ALS , 2008, FEBS letters.

[32]  H. Akiyama,et al.  TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. , 2007, Brain : a journal of neurology.

[33]  E. Buratti,et al.  Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. , 2008, Frontiers in bioscience : a journal and virtual library.

[34]  H. Arai,et al.  Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies , 2007, Brain Research.

[35]  E. Pioro,et al.  Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS , 2007, Neuroscience Letters.

[36]  S. Nakano,et al.  Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease , 2008, Acta Neuropathologica.

[37]  M. Strong The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis , 2008, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[38]  Holger Hummerich,et al.  Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia , 2005, Nature Genetics.

[39]  N. M. Reddy,et al.  Higher order arrangement of the eukaryotic nuclear bodies , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Geschwind,et al.  Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis , 2008, PLoS genetics.

[41]  J. Trojanowski,et al.  Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. , 2008, Archives of neurology.

[42]  D. Neary,et al.  Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43 , 2007, Acta Neuropathologica.

[43]  S. Sakoda,et al.  Nuclear TAR DNA Binding Protein 43 Expression in Spinal Cord Neurons Correlates With the Clinical Course in Amyotrophic Lateral Sclerosis , 2009, Journal of neuropathology and experimental neurology.

[44]  A. Singleton,et al.  TDP-43 Is Not a Common Cause of Sporadic Amyotrophic Lateral Sclerosis , 2008, PloS one.

[45]  西平 靖 Sporadic amyotrophic lateral sclerosis : two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions , 2009 .

[46]  N. Cairns,et al.  TDP‐43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations , 2007, Journal of neuropathology and experimental neurology.

[47]  J. Morris,et al.  TAR DNA-Binding Protein 43 Immunohistochemistry Reveals Extensive Neuritic Pathology in FTLD-U: A Midwest-Southwest Consortium for FTLD Study , 2008, Journal of neuropathology and experimental neurology.

[48]  R. Shiekhattar,et al.  The Microprocessor complex mediates the genesis of microRNAs , 2004, Nature.

[49]  A. Pestronk,et al.  TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[50]  B. McConkey,et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis , 2008, Nature Genetics.

[51]  Andrea D'Ambrogio,et al.  Structural determinants of the cellular localization and shuttling of TDP-43 , 2008, Journal of Cell Science.

[52]  A. Kakita,et al.  TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation , 2007, Acta Neuropathologica.

[53]  A. Pestronk,et al.  Inflammatory myopathies with mitochondrial pathology and protein aggregates , 2009, Journal of the Neurological Sciences.

[54]  J. Growdon,et al.  TAR-DNA Binding Protein 43 in Pick Disease , 2008, Journal of neuropathology and experimental neurology.

[55]  M. Freedman,et al.  Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis , 2009, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[56]  E. Bigio TAR DNA-binding protein-43 in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer disease , 2008, Acta Neuropathologica.

[57]  I-Fan Wang,et al.  TDP‐43, the signature protein of FTLD‐U, is a neuronal activity‐responsive factor , 2008, Journal of neurochemistry.

[58]  J. Trojanowski,et al.  Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. , 2006, The American journal of pathology.

[59]  J. Trojanowski,et al.  TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease , 2007, Acta Neuropathologica.

[60]  D. Dickson,et al.  FRONTOTEMPORAL LOBAR DEGENERATION WITH UPPER MOTOR NEURON DISEASE/ PRIMARY LATERAL SCLEROSIS , 2007, Neurology.

[61]  E. Bigio Update on Recent Molecular and Genetic Advances in Frontotemporal Lobar Degeneration , 2008, Journal of neuropathology and experimental neurology.

[62]  John L. Robinson,et al.  Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases , 2007, Acta Neuropathologica.

[63]  D. Dickson TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity , 2007, Acta Neuropathologica.

[64]  D. Dickson,et al.  TDP-43 in differential diagnosis of motor neuron disorders , 2007, Acta Neuropathologica.

[65]  M. Strong,et al.  TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein , 2007, Molecular and Cellular Neuroscience.

[66]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[67]  A. Kakita,et al.  Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology , 2008, Acta Neuropathologica.

[68]  P. Mcgeer,et al.  Colocalization of Transactivation-Responsive DNA-Binding Protein 43 and Huntingtin in Inclusions of Huntington Disease , 2008, Journal of neuropathology and experimental neurology.

[69]  M. Farrer,et al.  Pallidonigral TDP-43 pathology in Perry syndrome. , 2009, Parkinsonism & related disorders.

[70]  K. Josephs,et al.  TDP-43 is not present in brain tissue of patients with schizophrenia , 2009, Schizophrenia Research.

[71]  J. Trojanowski,et al.  Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease , 2007, Acta Neuropathologica.

[72]  J. Trojanowski,et al.  Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam , 2007, Acta Neuropathologica.

[73]  Y. Hirayasu,et al.  Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease , 2009, Acta Neuropathologica.

[74]  J. Trojanowski,et al.  Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies , 2009, Acta Neuropathologica.

[75]  J. Schneider,et al.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration , 2007, Acta Neuropathologica.

[76]  D. Dickson,et al.  TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease , 2007, Annals of neurology.

[77]  J. Trojanowski,et al.  TDP-43 Proteinopathies: Neurodegenerative Protein Misfolding Diseases without Amyloidosis , 2007, Neurosignals.

[78]  A. Isaacs,et al.  TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander , 2008, Mammalian Genome.

[79]  D. Neary,et al.  TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer’s disease and frontotemporal lobar degeneration , 2008, Acta Neuropathologica.

[80]  J. Trojanowski,et al.  TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. , 2007, Archives of neurology.

[81]  P. Deyn,et al.  Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS , 2009, Neurobiology of Aging.

[82]  Julie S. Snowden,et al.  Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype , 2006, Acta Neuropathologica.

[83]  L. Zinman,et al.  Evidence That TDP-43 is Not the Major Ubiquitinated Target Within the Pathological Inclusions of Amyotrophic Lateral Sclerosis , 2007, Journal of neuropathology and experimental neurology.

[84]  Murray Grossman,et al.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis , 2008, The Lancet Neurology.

[85]  J. Trojanowski,et al.  Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. , 2008, Archives of neurology.

[86]  Martin Lammens,et al.  TDP-43 accumulation is common in myopathies with rimmed vacuoles , 2009, Acta Neuropathologica.

[87]  D. Mann,et al.  Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis , 2008, Acta Neuropathologica.

[88]  E. Buratti,et al.  Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. , 2004, American journal of human genetics.

[89]  J. Trojanowski,et al.  TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2008, Archives of neurology.

[90]  H. Kretzschmar,et al.  TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD , 2008, Acta Neuropathologica.

[91]  C. Broeckhoven,et al.  Progranulin genetic variability contributes to amyotrophic lateral sclerosis , 2008, Neurology.

[92]  Hitoshi Takahashi,et al.  Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia , 2008, Acta Neuropathologica.

[93]  J. Trojanowski,et al.  TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system , 2008, Acta Neuropathologica.

[94]  Hans Förstl,et al.  No association of TDP-43 with sporadic frontotemporal dementia , 2009, Neurobiology of Aging.

[95]  D. Dickson,et al.  Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases , 2008, Acta Neuropathologica.

[96]  H. Akiyama,et al.  TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2006, Biochemical and biophysical research communications.

[97]  J. Collinge,et al.  Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases , 2008, Neuropathology and applied neurobiology.

[98]  Hitoshi Takahashi,et al.  Sporadic amyotrophic lateral sclerosis: Widespread multisystem degeneration with TDP‐43 pathology in a patient after long‐term survival on a respirator , 2009, Neuropathology : official journal of the Japanese Society of Neuropathology.

[99]  N. Cairns,et al.  ALS and FTLD: two faces of TDP‐43 proteinopathy , 2008, European journal of neurology.

[100]  J. Morris,et al.  TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. , 2007, The American journal of pathology.

[101]  R. Pamphlett,et al.  TDP-43 inclusions do not protect motor neurons from sporadic ALS , 2008, Acta Neuropathologica.

[102]  J. Trojanowski,et al.  Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations , 2007, Annals of neurology.

[103]  J. Trojanowski,et al.  Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2008, The American journal of pathology.

[104]  V. Meininger,et al.  Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis , 2008, Journal of Medical Genetics.

[105]  P. Reddi,et al.  A Novel CpG-free Vertebrate Insulator Silences the Testis-specific SP-10 Gene in Somatic Tissues , 2007, Journal of Biological Chemistry.

[106]  A. Kakita,et al.  TDP‐43 mutation in familial amyotrophic lateral sclerosis , 2008, Annals of neurology.

[107]  I-Fan Wang,et al.  TDP-43: an emerging new player in neurodegenerative diseases. , 2008, Trends in molecular medicine.