Skip to main content

Advertisement

SpringerLink
Log in

TDP-43 skeins show properties of amyloid in a subset of ALS cases

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Aggregation of TDP-43 proteins to form intracellular inclusions is the primary pathology in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (FTLD-TDP). Histologically, in the cerebral cortex and limbic regions of affected ALS and FTLD-TDP patients, these pathologies occur as a variety of cytoplasmic, neuritic and intranuclear TDP-43 inclusions. In the spinal cord and lower brainstem of ALS patients, the lesions form cytoplasmic dashes or complex filamentous and spherical profiles in addition to skein-like inclusions (SLI). Ultrastructurally, the morphology of TDP-43 inclusions is heterogeneous but mainly composed of loose bundles of 10- to 20-nm-diameter straight filaments associated with electron-dense granular material. All of these TDP-43 inclusions are generally described as disordered amorphous aggregations unlike the amyloid fibrils that characterize protein accumulations in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We here report that Thioflavin-S positive SLI are present in a subset of ALS cases, while TDP-43 inclusions outside the spinal cord lack the chemical properties of amyloid. Further, we examine the differential enrichment of fibrillar profiles in SLI of ALS cases by TDP-43 immuno-electron microscopy (immuno-EM). The demonstration that pathological TDP-43 can be amyloidogenic in situ suggests the following conclusions: (1) the conformational changes associated with TDP-43 aggregation are more complex than previously thought; (2) Thioflavin-S positive SLI may be composed primarily of filamentous ultrastructures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122(6):691–702. doi:10.1007/s00401-011-0911-2

    Article  PubMed  CAS  Google Scholar 

  2. Braak H, Ludolph A, Thal DR, Del Tredici K (2010) Amyotrophic lateral sclerosis: dash-like accumulation of phosphorylated TDP-43 in somatodendritic and axonal compartments of somatomotor neurons of the lower brainstem and spinal cord. Acta Neuropathol 120(1):67–74. doi:10.1007/s00401-010-0683-0

    Article  PubMed  CAS  Google Scholar 

  3. Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO, Safren N, Monteiro MJ, Toledo JB, Elman L, McCluskey L, Irwin DJ, Grossman M, Molina-Porcel L, Lee VM, Trojanowski JQ (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. doi:10.1007/s00401-012-0970-z

    Google Scholar 

  4. Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1(5):293–299

    Article  PubMed  CAS  Google Scholar 

  5. Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171(1):227–240 (pii: S0002-9440(10)61957-8)

    Google Scholar 

  6. Chen AK, Lin RY, Hsieh EZ, Tu PH, Chen RP, Liao TY, Chen W, Wang CH, Huang JJ (2010) Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J Am Chem Soc 132(4):1186–1187. doi:10.1021/ja9066207

    Article  PubMed  CAS  Google Scholar 

  7. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256. doi:10.1016/j.neuron.2011.09.011

    Article  PubMed  CAS  Google Scholar 

  8. Geser F, Lee VM, Trojanowski JQ (2010) Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30(2):103–112 (pii: NEU1091)

    Google Scholar 

  9. Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ (2009) Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 256(8):1205–1214. doi:10.1007/s00415-009-5069-7

    Article  PubMed  Google Scholar 

  10. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Baumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11(1):54–65. doi:10.1016/S1474-4422(11)70261-7

    Article  PubMed  CAS  Google Scholar 

  11. Goldschmidt L, Teng PK, Riek R, Eisenberg D (2010) Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci USA 107(8):3487–3492. doi:10.1073/pnas.0915166107

    Article  PubMed  CAS  Google Scholar 

  12. Guo W, Chen Y, Zhou X, Kar A, Ray P, Chen X, Rao EJ, Yang M, Ye H, Zhu L, Liu J, Xu M, Yang Y, Wang C, Zhang D, Bigio EH, Mesulam M, Shen Y, Xu Q, Fushimi K, Wu JY (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 18(7):822–830. doi:10.1038/nsmb.2053

    Article  PubMed  CAS  Google Scholar 

  13. Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64(1):60–70. doi:10.1002/ana.21425

    Article  PubMed  CAS  Google Scholar 

  14. Igaz LM, Kwong LK, Xu Y, Truax AC, Uryu K, Neumann M, Clark CM, Elman LB, Miller BL, Grossman M, McCluskey LF, Trojanowski JQ, Lee VM (2008) 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. Am J Pathol 173(1):182–194 (pii: ajpath.2008.080003)

    Google Scholar 

  15. King OD, Gitler AD, Shorter J (2012) The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. doi:10.1016/j.brainres.2012.01.016

    Google Scholar 

  16. Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13(1):38–50. doi:10.1038/nrn3121

    CAS  Google Scholar 

  17. Levine H 3rd, Walker LC (2010) Molecular polymorphism of Abeta in Alzheimer’s disease. Neurobiol Aging 31(4):542–548. doi:10.1016/j.neurobiolaging.2008.05.026

    Article  PubMed  CAS  Google Scholar 

  18. Lin WL, Dickson DW (2008) Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol 116(2):205–213. doi:10.1007/s00401-008-0408-9

    Article  PubMed  CAS  Google Scholar 

  19. Llewellyn-Smith IJ, Minson JB (1992) Complete penetration of antibodies into vibratome sections after glutaraldehyde fixation and ethanol treatment: light and electron microscopy for neuropeptides. J Histochem Cytochem 40(11):1741–1749

    Article  PubMed  CAS  Google Scholar 

  20. Lowe J (1994) New pathological findings in amyotrophic lateral sclerosis. J Neurol Sci 124(Suppl):38–51

    Article  PubMed  Google Scholar 

  21. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122(1):111–113. doi:10.1007/s00401-011-0845-8

    Article  PubMed  Google Scholar 

  22. Marshak DW (1992) Localization of immunoreactive tyrosine hydroxylase in the goldfish retina with pre-embedding immunolabeling with one-nanometer colloidal gold particles and gold toning. J Histochem Cytochem 40(10):1465–1470

    Article  PubMed  CAS  Google Scholar 

  23. Mizusawa H, Nakamura H, Wakayama I, Yen SH, Hirano A (1991) Skein-like inclusions in the anterior horn cells in motor neuron disease. J Neurol Sci 105(1):14–21

    Article  PubMed  CAS  Google Scholar 

  24. Mori F, Tanji K, Miki Y, Kakita A, Takahashi H, Wakabayashi K (2010) Relationship between Bunina bodies and TDP-43 inclusions in spinal anterior horn in amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 36(4):345–352. doi:10.1111/j.1365-2990.2010.01081.x

    Article  PubMed  CAS  Google Scholar 

  25. Mori F, Tanji K, Zhang HX, Nishihira Y, Tan CF, Takahashi H, Wakabayashi K (2008) Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 116(2):193–203. doi:10.1007/s00401-008-0396-9

    Article  PubMed  CAS  Google Scholar 

  26. Nakano I (2011) Frontotemporal lobar degeneration (FTLD) concept and classification update. Rinsho Shinkeigaku 51(11):844–847

    Article  PubMed  Google Scholar 

  27. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51(6):1546–1554

    Article  PubMed  CAS  Google Scholar 

  28. Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VM (2007) TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis. Arch Neurol 64(10):1388–1394 (pii: 64/10/1388)

    Google Scholar 

  29. Neumann 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 (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133 (pii: 314/5796/130)

    Google Scholar 

  30. Polymenidou M, Cleveland DW (2012) Prion-like spread of protein aggregates in neurodegeneration. J Exp Med 209(5):889–893. doi:10.1084/jem.20120741

    Article  PubMed  CAS  Google Scholar 

  31. Romijn HJ, van Uum JF, Breedijk I, Emmering J, Radu I, Pool CW (1999) Double immunolabeling of neuropeptides in the human hypothalamus as analyzed by confocal laser scanning fluorescence microscopy. J Histochem Cytochem 47(2):229–236

    Article  PubMed  CAS  Google Scholar 

  32. Sasaki S, Takeda T, Shibata N, Kobayashi M (2010) Alterations in subcellular localization of TDP-43 immunoreactivity in the anterior horns in sporadic amyotrophic lateral sclerosis. Neurosci Lett 478(2):72–76. doi:10.1016/j.neulet.2010.04.068

    Article  PubMed  CAS  Google Scholar 

  33. Schmidt ML, Schuck T, Sheridan S, Kung MP, Kung H, Zhuang ZP, Bergeron C, Lamarche JS, Skovronsky D, Giasson BI, Lee VM, Trojanowski JQ (2001) The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse beta-pleated sheet structures in postmortem human neurodegenerative disease brains. Am J Pathol 159(3):937–943 (pii: S0002-9440(10)61769-5)

    Google Scholar 

  34. Sipe JD (1992) Amyloidosis. Annu Rev Biochem 61:947–975. doi:10.1146/annurev.bi.61.070192.004503

    Article  PubMed  CAS  Google Scholar 

  35. Thorpe JR, Tang H, Atherton J, Cairns NJ (2008) Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J Neural Transm 115(12):1661–1671. doi:10.1007/s00702-008-0137-1

    Article  PubMed  CAS  Google Scholar 

  36. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7(5):409–416 (pii: S1474-4422(08)70071-1)

    Google Scholar 

  37. Wilcock DM, Gordon MN, Morgan D (2006) Quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with Congo red histochemical stain. Nat Protoc 1(3):1591–1595. doi:10.1038/nprot.2006.277

    Article  PubMed  CAS  Google Scholar 

  38. Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD, Van Deerlin VM (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67(2):161–170. doi:10.1001/archneurol.2009.328

Download references

Acknowledgments

We thank our many TDP-43 colleagues in the Center for Neurodegenerative Disease Research (CNDR) and the Department of Neurology for extensive collaborations that provided essential input at many stages of our research on TDP-43 since 2006. In particular we thank Dr. Edward B. Lee, Ms. Theresa Schuck and Mr. Michael Partain for their input on these studies which were supported by the National Institutes of Health (AG10124, AG17586, K08AG039510, and training grant T32 AG00255). Virginia M-Y. Lee is the John H. Ware III Chair of Alzheimer’s Research and John Q. Trojanowski is the William Maul Measey-Truman G. Schnabel, Jr., MD Professor of Geriatric Medicine and Gerontology. The authors are especially grateful to the families and patients affected by these diseases, without whose donations, this research would not be possible.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer’s Disease Core Center, Institute on Aging, Perelman School of Medicine at the University of Pennsylvania, Maloney Building, 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    John L. Robinson, Felix Geser, Anna Stieber, Mfon Umoh, Linda K. Kwong, Vivianna M. Van Deerlin, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany

    Felix Geser

Authors
  1. John L. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix Geser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Stieber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mfon Umoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Linda K. Kwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vivianna M. Van Deerlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Virginia M.-Y. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John Q. Trojanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Q. Trojanowski.

Additional information

J. L. Robinson, F. Geser and A. Stieber made equal contributions.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (DOCX 1.297 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robinson, J.L., Geser, F., Stieber, A. et al. TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol 125, 121–131 (2013). https://doi.org/10.1007/s00401-012-1055-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-012-1055-8

Keywords

Search

Navigation