Acta Neuropathologica

, Volume 125, Issue 1, pp 121–131 | Cite as

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

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

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.

Keywords

TDP-43 Amyloid Skein Amyotrophic lateral sclerosis ALS Frontotemporal lobar degeneration FTLD-TDP 

Notes

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.

Supplementary material

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Supplementary material (DOCX 1.297 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • John L. Robinson
    • 1
  • Felix Geser
    • 1
    • 2
  • Anna Stieber
    • 1
  • Mfon Umoh
    • 1
  • Linda K. Kwong
    • 1
  • Vivianna M. Van Deerlin
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer’s Disease Core CenterInstitute on Aging, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of NeurologyCenter for Biomedical Research, University of UlmUlmGermany

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