TDP-43 in Familial and Sporadic Frontotemporal Lobar Degeneration with Ubiquitin Inclusions
2007; Elsevier BV; Volume: 171; Issue: 1 Linguagem: Inglês
10.2353/ajpath.2007.070182
ISSN1525-2191
AutoresNigel J. Cairns, Manuela Neumann, Eileen H. Bigio, Ida E. Holm, Dirk Troost, Kimmo J. Hatanpaa, Chan Foong, Charles L. White, Julie A. Schneider, Hans A. Kretzschmar, Deborah Carter, Lisa Taylor‐Reinwald, Katherine Paulsmeyer, Jeffrey Strider, Michael A. Gitcho, Alison Goate, John C. Morris, Manjari Mishra, Linda K. Kwong, Anna Stieber, Yan Xu, Mark S. Forman, John Q. Trojanowski, Virginia M.‐Y. Lee, Ian R. Mackenzie,
Tópico(s)Neurological diseases and metabolism
ResumoTAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis. The frontotemporal dementias (FTDs) are a clinically, genetically, and neuropathologically heterogeneous group of diseases accounting for up to 20% of presenile dementia cases. FTD is characterized by behavioral and/or language dysfunction and may co-occur with motor neuron disease (MND).1Neary D Snowden JS Mann DM Classification and description of frontotemporal dementias.Ann NY Acad Sci. 2000; 920: 46-51Crossref PubMed Scopus (72) Google Scholar, 2Neary D Snowden JS Mann DM Northen B Goulding PJ Macdermott N Frontal lobe dementia and motor neuron disease.J Neurol Neurosurg Psychiatry. 1990; 53: 23-32Crossref PubMed Scopus (426) Google Scholar Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) is the most common underlying pathology in FTD with and without MND.3Lipton AM White III, CL Bigio EH Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration.Acta Neuropathol (Berl). 2004; 108: 379-385Crossref PubMed Scopus (171) Google Scholar TAR DNA-binding protein 43 (TDP-43), a nuclear protein implicated in exon skipping and transcription regulation,4Buratti E Dork T Zuccato E Pagani F Romano M Baralle FE Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.EMBO J. 2001; 20: 1774-1784Crossref PubMed Scopus (495) Google Scholar, 5Buratti E Brindisi A Pagani F Baralle FE 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.Am J Hum Genet. 2004; 74: 1322-1325Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 6Mercado PA Ayala YM Romano M Buratti E Baralle FE Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene.Nucleic Acids Res. 2005; 33: 6000-6010Crossref PubMed Scopus (194) Google Scholar was recently identified as a major protein component of the ubiquitin-immunoreactive inclusions characteristic of sporadic and familial FTLD-U, with and without MND, as well as in sporadic amyotrophic lateral sclerosis (ALS)7Arai T Hasegawa M Akiyama H Ikeda K Nonaka T Mori H Mann D Tsuchiya K Yoshida M Hashizume Y Oda T TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Biochem Biophys Res Commun. 2006; 351: 602-611Crossref PubMed Scopus (1848) Google Scholar, 8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar and has been rapidly confirmed by others.9Davidson Y Kelley T Mackenzie IR Pickering-Brown S Du Plessis D Neary D Snowden JS Mann DM Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43.Acta Neuropathol (Berl). 2007; 113: 521-533Crossref PubMed Scopus (266) Google Scholar, 10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar, 11Neumann M Kwong LK Truax AC Vanmassenhove B Kretzschmar HA Van Deerlin VM Clark CM Grossman M Miller BL Trojanowski JQ Lee VMY TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions.J Neuropathol Exp Neurol. 2007; 66: 177-183Crossref PubMed Scopus (179) Google Scholar TDP-43 in these disorders is abnormally phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and is recovered only from areas with ubiquitin-immunoreactive inclusions, including hippocampus, neocortex, and spinal cord.8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar Therefore, the presence of abnormal aggregates of phosphorylated and ubiquitinated TDP-43 defines a novel class of neurodegenerative diseases that we propose to call “TDP-43 proteinopathies” that includes FTLD-U, FTLD-MND, and ALS. The neuropathology of these conditions is characterized by ubiquitin- and TDP-43-positive neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions (NIIs), dystrophic neurites (DNs), and glial cytoplasmic inclusions8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar, 10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar, 11Neumann M Kwong LK Truax AC Vanmassenhove B Kretzschmar HA Van Deerlin VM Clark CM Grossman M Miller BL Trojanowski JQ Lee VMY TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions.J Neuropathol Exp Neurol. 2007; 66: 177-183Crossref PubMed Scopus (179) Google Scholar, 12Woulfe J Kertesz A Munoz DG Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions.Acta Neuropathol (Berl). 2001; 102: 94-102PubMed Google Scholar that are negative for tau, α-synuclein, β-amyloid, neuronal intermediate filaments, and expanded polyglutamines. The variability in the morphological types of neuronal inclusions, their distribution, density, and immunohistochemical profile has led to the development of the classification of FTLD-U into four pathological subtypes.8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar, 10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar, 13Forman MS Mackenzie IR Cairns NJ Swanson E Boyer PJ Drachman DA Jhaveri BS Karlawish JH Pestronk A Smith TW Tu PH Watts GD Markesbery WR Smith CD Kimonis VE Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.J Neuropathol Exp Neurol. 2006; 65: 571-581Crossref PubMed Scopus (197) Google Scholar, 14Sampathu DM Neumann M Kwong LK Chou TT Micsenyi M Truax A Bruce J Grossman M Trojanowski JQ Lee VM Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies.Am J Pathol. 2006; 169: 1343-1352Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Recently, the molecular genetic basis of non-tau familial FTD linked to chromosome 17 was discovered as being mutations in the progranulin gene (PGRN).15Baker M Mackenzie IR Pickering-Brown SM Gass J Rademakers R Lindholm C Snowden J Adamson J Sadovnick AD Rollinson S Cannon A Dwosh E Neary D Melquist S Richardson A Dickson D Berger Z Eriksen J Robinson T Zehr C Dickey CA Crook R McGowan E Mann D Boeve B Feldman H Hutton M Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.Nature. 2006; 442: 916-919Crossref PubMed Scopus (1587) Google Scholar, 16Cruts M Gijselinck I van der ZJ Engelborghs S Wils H Pirici D Rademakers R Vandenberghe R Dermaut B Martin JJ van Duijn C Peeters K Sciot R Santens P De Pooter T Mattheijssens M van den BM Cuijt I Vennekens K De Deyn PP Kumar-Singh S Van Broeckhoven C Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.Nature. 2006; 442: 920-924Crossref PubMed Scopus (1223) Google Scholar, 17Mukherjee O Pastor P Cairns NJ Chakraverty S Kauwe JS Shears S Behrens MI Budde J Hinrichs AL Norton J Levitch D Taylor-Reinwald L Gitcho M Tu PH Tenenholz GL Liscic RM Armendariz J Morris JC Goate AM HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.Ann Neurol. 2006; 60: 314-322Crossref PubMed Scopus (176) Google Scholar The neuropathology in these cases is FTLD-U with ubiquitin-positive neurites, NCI and, most characteristically, NII.17Mukherjee O Pastor P Cairns NJ Chakraverty S Kauwe JS Shears S Behrens MI Budde J Hinrichs AL Norton J Levitch D Taylor-Reinwald L Gitcho M Tu PH Tenenholz GL Liscic RM Armendariz J Morris JC Goate AM HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.Ann Neurol. 2006; 60: 314-322Crossref PubMed Scopus (176) Google Scholar, 18Mackenzie IR Baker M Pickering-Brown S Hsiung GY Lindholm C Dwosh E Gass J Cannon A Rademakers R Hutton M Feldman HH The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.Brain. 2006; 129: 3081-3090Crossref PubMed Scopus (255) Google Scholar, 19Behrens MI Mukherjee O Tu PH Liscic RM Grinberg LT Carter D Paulsmeyer K Taylor-Reinwald L Gitcho M Norton JB Chakraverty S Goate AM Morris JC Cairns NJ Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.Alzheimer Dis Assoc Disord. 2007; 21: 1-7Crossref PubMed Scopus (57) Google Scholar As demonstrated by immunohistochemical and biochemical investigation, the ubiquitinated pathological protein in these cases is not progranulin but TDP-43.8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar, 9Davidson Y Kelley T Mackenzie IR Pickering-Brown S Du Plessis D Neary D Snowden JS Mann DM Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43.Acta Neuropathol (Berl). 2007; 113: 521-533Crossref PubMed Scopus (266) Google Scholar Pathological TDP-43 is detected biochemically in both affected gray and white matter, suggesting that both glial and neuronal pathology may contribute to the pathogenesis of FTLD-U caused by PGRN mutations.8Neumann M Sampathu DM Kwong LK Truax AC Micsenyi MC Chou TT Bruce J Schuck T Grossman M Clark CM McCluskey LF Miller BL Masliah E Mackenzie IR Feldman H Feiden W Kretzschmar HA Trojanowski JQ Lee VM Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4411) Google Scholar, 11Neumann M Kwong LK Truax AC Vanmassenhove B Kretzschmar HA Van Deerlin VM Clark CM Grossman M Miller BL Trojanowski JQ Lee VMY TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions.J Neuropathol Exp Neurol. 2007; 66: 177-183Crossref PubMed Scopus (179) Google Scholar Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia is a rare autosomal dominant disorder caused by mutations in the valosin-containing protein gene (VCP).10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar, 13Forman MS Mackenzie IR Cairns NJ Swanson E Boyer PJ Drachman DA Jhaveri BS Karlawish JH Pestronk A Smith TW Tu PH Watts GD Markesbery WR Smith CD Kimonis VE Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.J Neuropathol Exp Neurol. 2006; 65: 571-581Crossref PubMed Scopus (197) Google Scholar, 20Watts GD Wymer J Kovach MJ Mehta SG Mumm S Darvish D Pestronk A Whyte MP Kimonis VE Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.Nat Genet. 2004; 36: 377-381Crossref PubMed Scopus (1103) Google Scholar VCP, a member of the AAA-ATPase gene super family (ATPase associated with diverse cellular activities), has multiple cellular functions, including acting as a molecular chaperone in endoplasmic reticulum-associated protein degradation, stress response, programmed cell death, and interactions with the ubiquitin-proteasome system.21Wang Q Song C Li CC Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions.J Struct Biol. 2004; 146: 44-57Crossref PubMed Scopus (256) Google Scholar The neuropathology in inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia is a unique subtype of FTLD-U characterized by numerous NIIs and relatively few NCIs and DNs.10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar, 13Forman MS Mackenzie IR Cairns NJ Swanson E Boyer PJ Drachman DA Jhaveri BS Karlawish JH Pestronk A Smith TW Tu PH Watts GD Markesbery WR Smith CD Kimonis VE Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.J Neuropathol Exp Neurol. 2006; 65: 571-581Crossref PubMed Scopus (197) Google Scholar Once again, the ubiquitinated pathology is not primarily composed of the mutated protein (VCP) but rather TDP-43.10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar Phosphorylated TDP-43 is detected only in the insoluble brain extracts from affected regions, indicating that the VCP gene mutations cause a dominant-negative loss of function or alteration of VCP function, leading to impaired metabolism of TDP-43.10Neumann M Mackenzie IR Cairns NJ Boyer PJ Markesbery WR Smith CD Taylor J Paul Kretzschmar HA Kimonis V Forman MS TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP mutations.J Neuropathol Exp Neurol. 2007; 66: 152-157Crossref PubMed Scopus (273) Google Scholar Mutations in the charged multivesicular body protein 2B gene (CHMP2B) were recently identified as the cause of FTD linked to chromosome 3 in a large Danish pedigree.22Skibinski G Parkinson NJ Brown JM Chakrabarti L Lloyd SL Hummerich H Nielsen JE Hodges JR Spillantini MG Thusgaard T Brandner S Brun A Rossor MN Gade A Johannsen P Sorensen SA Gydesen S Fisher EM Collinge J Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.Nat Genet. 2005; 37: 806-808Crossref PubMed Scopus (671) Google Scholar Human CHMP2B is a protein of 213 amino acids with a predicted coil-coil domain and is a component of the endosomal secretory complex III required for transport. Neuropathology was originally described as “dementia lacking distinctive histopathology,” but more recent studies have revealed ubiquitin-positive granular NCIs in frontal neocortex and hippocampus.23Holm IE Ubiquitin-positive inclusions in frontotemporal dementia linked to chromosome 3 (FTD-3).Brain Pathol. 2006; 16: S43Google Scholar TDP-43 immunohistochemistry, electron microscopy, and biochemistry have not previously been undertaken in these cases. Recently, a new genetic locus on chromosome 9p for familial FTD-MND has been described.24Morita M Al Chalabi A Andersen PM Hosler B Sapp P Englund E Mitchell JE Habgood JJ de Belleroche J Xi J Jongjaroenprasert W Horvitz HR Gunnarsson LG Brown Jr, RH A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia.Neurology. 2006; 66: 839-844Crossref PubMed Scopus (307) Google Scholar, 25Vance C Al Chalabi A Ruddy D Smith BN Hu X Sreedharan J Siddique T Schelhaas HJ Kusters B Troost D Baas F de Jong V Shaw CE Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3.Brain. 2006; 129: 868-876Crossref PubMed Scopus (326) Google Scholar In one family, candidate gene sequencing revealed the presence of a putative disease segregating stop codon mutation (Q342X) in the intraflagellar transport protein 74 gene (IFT74).26Momeni P Schymick J Jain S Cookson MR Cairns NJ Greggio E Greenway MJ Berger S Pickering-Brown S Chio A Fung HC Holtzman DM Huey ED Wassermann EM Adamson J Hutton ML Rogaeva E St George-Hyslop P Rothstein JD Hardiman O Grafman J Singleton A Hardy J Traynor BJ Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD.BMC Neurol. 2006; 6: 44Crossref PubMed Scopus (74) Google Scholar IFT74 is a 600-amino acid protein with a coiled-coil domain-containing protein that localizes to the intracellular vesicle compartment and is a component of the intraflagellar transport system responsible for vesicular transport of material synthesized within the cell body into and along dendrites and axons. Neuropathology in a single case with the IFT74 gene mutation was reported as showing all of the signs of FTLD-U (ubiquitinated NCI, DN, and NII).26Momeni P Schymick J Jain S Cookson MR Cairns NJ Greggio E Greenway MJ Berger S Pickering-Brown S Chio A Fung HC Holtzman DM Huey ED Wassermann EM Adamson J Hutton ML Rogaeva E St George-Hyslop P Rothstein JD Hardiman O Grafman J Singleton A Hardy J Traynor BJ Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD.BMC Neurol. 2006; 6: 44Crossref PubMed Scopus (74) Google Scholar TDP-43 immunohistochemistry and biochemistry have not previously been reported in this or other chromosome 9-linked FTD families. Therefore, previous studies indicate that TDP-43-immunoreactive inclusions constitute a common pathological finding linking many cases of sporadic FTLD-U, familial FTLD-U with PGRN and VCP mutations, and FTLD-MND. However, each of the aforementioned studies included relatively small numbers of cases in each disease category. The aims of the present study were as follows: 1) to define the frequency of TDP-43 proteinopathy in a much larger collection of familial and sporadic cases of FTLD-U and FTLD-MND, collected at multiple sites in North America and Europe; 2) to determine whether FTLD-U in reported families linked to chromosome 9p and FTLD-U linked to chromosome 3 are TDP-43 proteinopathies; and 3) to examine the presence of pathological TDP-43 in a wider range of FTLDs and other neurodegenerative conditions. Brain tissues from clinically and neuropathologically characterized cases of sporadic and familial FTLD-U, with or without MND, other FTLDs, and other neurodegenerative diseases were obtained from Canada, Denmark, Germany, The Netherlands, and the United States (Table 1; Supplemental Table 1, see ). Cases of FTLD-U showed characteristic pathology3Lipton AM White III, CL Bigio EH Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration.Acta Neuropathol (Berl). 2004; 108: 379-385Crossref PubMed Scopus (171) Google Scholar, 17Mukherjee O Pastor P Cairns NJ Chakraverty S Kauwe JS Shears S Behrens MI Budde J Hinrichs AL Norton J Levitch D Taylor-Reinwald L Gitcho M Tu PH Tenenholz GL Liscic RM Armendariz J Morris JC Goate AM HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.Ann Neurol. 2006; 60: 314-322Crossref PubMed Scopus (176) Google Scholar, 18Mackenzie IR Baker M Pickering-Brown S Hsiung GY Lindholm C Dwosh E Gass J Cannon A Rademakers R Hutton M Feldman HH The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.Brain. 2006; 129: 3081-3090Crossref PubMed Scopus (255) Google Scholar, 19Behrens MI Mukherjee O Tu PH Liscic RM Grinberg LT Carter D Paulsmeyer K Taylor-Reinwald L Gitcho M Norton JB Chakraverty S Goate AM Morris JC Cairns NJ Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.Alzheimer Dis Assoc Disord. 2007; 21: 1-7Crossref PubMed Scopus (57) Google Scholar, 27McKhann GM Albert MS Grossman M Miller B Dickson D Trojanowski JQ Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease.Arch Neurol. 2001; 58: 1803-1809Crossref PubMed Scopus (1305) Google Scholar and had a clinical diagnosis of one of the FTD subtypes (including frontal variant FTD, primary progressive aphasia, or corticobasal syndrome), MND with dementia, or simply “dementia.”1Neary D Snowden JS Mann DM Classification and description of frontotemporal dementias.Ann NY Acad Sci. 2000; 920: 46-51Crossref PubMed Scopus (72) Google Scholar, 2Neary D Snowden JS Mann DM Northen B Goulding PJ Macdermott N Frontal lobe dementia and motor neuron disease.J Neurol Neurosurg Psychiatry. 1990; 53: 23-32Crossref PubMed Scopus (426) Google Scholar, 27McKhann GM Albert MS Grossman M Miller B Dickson D Trojanowski JQ Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease.Arch Neurol. 2001; 58: 1803-1809Crossref PubMed Scopus (1305) Google Scholar, 28Dickson DW Bergeron C Chin SS Duyckaerts C Horoupian D Ikeda K Jellinger K Lantos PL Lippa CF Mirra SS Tabaton M Vonsattel JP Wakabayashi K Litvan I Office of Rare Diseases neuropathologic criteria for corticobasal degeneration.J Neuropathol Exp Neurol. 2002; 61: 935-946Crossref PubMed Scopus (546) Google Scholar Those with the primary clinical diagnosis of either ALS or MND,29Brooks BR El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis: Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors.J Neurol Sci. 1994; 124: 96-107Abstract Full Text PDF PubMed Scopus (1975) Google Scholar in the absence of clinical dementia, were excluded from this study. The FTLD-U group included 1) familial cases with PGRN,17Mukherjee O Pastor P Cairns NJ Chakraverty S Kauwe JS Shears S Behrens MI Budde J Hinrichs AL Norton J Levitch D Taylor-Reinwald L Gitcho M Tu PH Tenenholz GL Liscic RM Armendariz J Morris JC Goate AM HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.Ann Neurol. 2006; 60: 314-322Crossref PubMed Scopus (176) Google Scholar, 18Mackenzie IR Baker M Pickering-Brown S Hsiung GY Lindholm C Dwosh E Gass J Cannon A Rademakers R Hutton M Feldman HH The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.Brain. 2006; 129: 3081-3090Crossref PubMed Scopus (255) Google Scholar, 19Behrens MI Mukherjee O Tu PH Liscic RM Grinberg LT Carter D Paulsmeyer K Taylor-Reinwald L Gitcho M Norton JB Chakraverty S Goate AM Morris JC Cairns NJ Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation.Alzheimer Dis Assoc Disord. 2007; 21: 1-7Crossref PubMed Scopus (57) Google Scholar, 30Gass J Cannon A Mackenzie IR Boeve B Baker M Adamson J Crook R Melquist S Kuntz K Petersen R Josephs K Pickering-Brown SM Graff-Radford N Uitti R Dickson D Wszolek Z Gonzalez J Beach TG Bigio E Johnson N Weintraub S Mesulam M White III, CL Woodruff B Caselli R Hsiung GY Feldman H Knopman D Hutton M Rademakers R Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.Hum Mol Genet. 2006; 15: 2988-3001Crossref PubMed Scopus (482) Google ScholarVCP,11Neumann M Kwong LK Truax AC Vanmassenhove B Kretzschmar HA Van Deerlin VM Clark CM Grossman M Miller BL Trojanowski JQ Lee VMY TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions.J Neuropathol Exp Neurol. 2007; 66: 177-183Crossref PubMed Scopus (179) Google Scholar, 13Forman MS Mackenzie IR Cairns NJ Swanson E Boyer PJ Drachman DA Jhaveri BS Karlawish JH Pestronk A Smith TW Tu PH Watts GD Markesbery WR Smith CD Kimonis VE Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.J Neuropathol Exp Neurol. 2006; 65: 571-581Crossref PubMed Scopus (197) Google Scholar and CHMP2B22Skibinski G Parkinson NJ Brown JM Chakrabarti L Lloyd SL Hummerich H Nielsen JE Hodges JR Spillantini MG Thusgaard T Brandner S Brun A Rossor MN Gade A Johannsen P Sorensen SA Gydesen S Fisher EM Collinge J Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.Nat Genet. 2005; 37: 806-808Crossref PubMed Scopus (671) Google Scholar mutations and cases linked to chromosome 9p,24Morita M Al Chalabi A Andersen PM Hosler B Sapp P Englund E Mitchell JE Habgood JJ de Belleroche J Xi J Jongjaroenprasert W Horvitz HR Gunnarsson LG Brown Jr, RH A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia.Neurology. 2006; 66: 839-844Crossref PubMed Scopus (307) Google Scholar, 25Vance C Al Chalabi A Ruddy D Smith BN Hu X Sreedharan J Siddique T Schelhaas HJ Kusters B Troost D Baas F de Jong V Shaw CE Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3.Brain. 2006; 129: 868-876Crossref PubMed Scopus (326) Google Scholar including one case with IFT74 gene mutation26M
Referência(s)