Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy (original) (raw)

Abstract

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of the pathological inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy, also called FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and motor neuron disease (MND). TDP-43 is predominantly expressed in the nucleus and regulates gene expression and splicing. In FTLD with TDP-43 proteinopathy, neuronal inclusions present variably as cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and intranuclear inclusions (NIIs), leading to a fourfold neuropathological classification correlating with genotype. There have been few fine structural studies of these inclusions. Thus, we undertook an immunoelectron microscopic study of FTLD with TDP-43 proteinopathy, including sporadic and familial cases with progranulin (GRN) mutation. TDP-43-immunoreactive inclusions comprised two components: granular and filamentous. Filament widths, expressed as mean (range) were: NCI, 9 nm (4–16 nm); DN, 10 nm (5–16 nm); NII, 18 nm (9–50 nm). Morphologically distinct inclusion components may reflect the process of TDP-43 aggregation and interaction with other proteins: determining these latter may contribute towards understanding the heterogeneous pathogenesis of FTLD with TDP-43 proteinopathy.

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References

• Amador-Ortiz CLW, Ahmed Z, Personett D et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445
  Article PubMed CAS Google Scholar
• Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611
  Article PubMed CAS Google Scholar
• Armstrong RAL, Lantos PL, Cairns NJ (2008) What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease? Neuropathology PM:18433435
• Ayala YM, Pantano S, D’Ambrogio A et al (2005) Human, Drosophila, and C elegans TDP 43: nucleic acid binding properties and splicing regulatory function. J Mol Biol 348:575–588
  Article PubMed CAS Google Scholar
• Brandmeir NJ, Geser F, Kwong LK et al (2008) Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115:123–131
  Article PubMed Google Scholar
• Buratti E, Baralle FE (2001) 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 276:36337–36343
  Article PubMed CAS Google Scholar
• Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20:1774–1784
  Article PubMed CAS Google Scholar
• Buratti E, Brindisi A, Pagani F, Baralle FE (2004) 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 74:1322–1325
  Article PubMed CAS Google Scholar
• Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE (2005) 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. J Biol Chem 280:37572–37584
  Article PubMed CAS Google Scholar
• Cairns NJ, Bigio EH, Mackenzie IRA et al (2007a) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22
  Article PubMed Google Scholar
• Cairns NJ, Neumann M, Bigio EH et al (2007b) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240
  Article PubMed CAS Google Scholar
• Davidson Y, Kelley T, Mackenzie IRA et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533
  Article PubMed CAS Google Scholar
• Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145
  Article PubMed CAS Google Scholar
• Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538
  Article PubMed CAS Google Scholar
• Hasegawa MAT, Nonaka T, Kametani F et al (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70
  Article PubMed CAS Google Scholar
• Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294
  Article PubMed CAS Google Scholar
• Ignatius SH, Wu F, Harrich D, Garciamartinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human-immunodeficiency-virus type-1 Tar DNA-sequence motifs. J Virol 69:3584–3596
  Google Scholar
• Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18:S2–S12
  Article PubMed Google Scholar
• Johnson BS, McCaffery JM, Lindquist S, Gitler AD (2008) A yeast TDP-43 proteinopathy model: exploring the molecular determinants of TDR-43 aggregation and cellular toxicity. Proc Natl Acad Sci USA 105:6439–6444
  Article PubMed CAS Google Scholar
• Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574
  Article PubMed CAS Google Scholar
• Lin W-L, Dickson DW (2008) Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol 116:205–213
  Article PubMed CAS Google Scholar
• Mosaheb S, Thorpe JR, Hashemzadeh-Bonehi L, Bigio EH, Gearing M, Cairns NJ (2005) Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease. Acta Neuropathol 110:360–368
  Article PubMed Google Scholar
• Mukherjee OP, Pastor P, Cairns NJ et al (2006) 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 60:314–322
  Article PubMed CAS Google Scholar
• Mukherjee O, Wang J, Gitcho M et al (2008) Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 29:512–521
  Article PubMed CAS Google Scholar
• Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229
  Article PubMed CAS Google Scholar
• Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
  Article PubMed CAS Google Scholar
• Seelaar H, Schelhaas HJ, Azmani A et al (2007) TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without progranulin mutations. Brain 130:1375–1385
  Article PubMed Google Scholar
• Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672
  Article PubMed CAS Google Scholar
• Thorpe JR (1999) The application of LR gold resin for immunogold labelling. Chapter 6 In: MA Hajibagheri (ed) Electron microscopy methods and protocols. Methods in molecular biology Series, vol 117. pp 99–110
• Thorpe JR, Morley SJ, Rulten SL (2001) Utilising the peptidyl- prolyl cis-trans isomerase Pin1 as a probe of its phosphorylated target proteins: examples of binding to nuclear proteins in a human kidney cell line and to Tau in Alzheimer’s diseased brain. J Histochem Cytochem 49:97–108
  PubMed CAS Google Scholar
• Thorpe JR, Mosaheb S, Hashemzadeh-Bonehi L et al (2004) Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias. Neurobiol Dis 17:237–249
  Article PubMed CAS Google Scholar
• Uryu KN-Y, Forman H, Kwong MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropath Exp Neurol 67:555–564
  Article PubMed CAS Google Scholar
• Zuccato E, Buratti E, Stuani C, Baralle FE, Pagani F (2004) An intronic polypyrimidine-rich element downstream of the donor site modulates cystic fibrosis transmembrane conductance regulator exon 9 alternative splicing. J Biol Chem 279:16980–16988
  Article PubMed CAS Google Scholar

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Acknowledgments

We thank the families of patients whose generosity made this research possible. We acknowledge the staff of the Alzheimer’s Disease Research Center Neuropathology Laboratory, Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, USA and Max Allin, University of Sussex, for technical assistance. Support for this work was provided by grants from the Wellcome Trust, UK, (GR066166AIA) to JRT and NJC, and the National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) to NJC.

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Authors and Affiliations

1. Electron Microscope Division, The Sussex Centre for Advanced Microscopy, John Maynard-Smith Building, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK
   Julian R. Thorpe, Helen Tang & Joe Atherton
2. Alzheimer’s Disease Research Center, Departments of Neurology and Pathology and Immunology, Washington University School of Medicine, St Louis, MI, 63110, USA
   Nigel J. Cairns

Authors

1. Julian R. Thorpe
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2. Helen Tang
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3. Joe Atherton
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4. Nigel J. Cairns
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Correspondence toJulian R. Thorpe.

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Supported by grants to JRT and NJC from the Wellcome Trust (GR066166AIA), and National Institute on Aging of the National Institutes of Health (P50 AG05681 and P01 AG03991) to NJC.

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Thorpe, J.R., Tang, H., Atherton, J. et al. Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy.J Neural Transm 115, 1661–1671 (2008). https://doi.org/10.1007/s00702-008-0137-1

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• Received: 27 June 2008
• Accepted: 05 October 2008
• Published: 31 October 2008
• Issue Date: December 2008
• DOI: https://doi.org/10.1007/s00702-008-0137-1

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