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Amyotrophic lateral sclerosis—a model of corticofugal axonal spread

Nature Reviews Neurology volume 9, pages 708–714 (2013)Cite this article

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Abstract

The pathological process underlying amyotrophic lateral sclerosis (ALS) is associated with the formation of cytoplasmic inclusions consisting mainly of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43), which plays an essential part in the pathogenesis of ALS. Preliminary evidence indicates that neuronal involvement progresses at different rates, but in a similar sequence, in different patients with ALS. This observation supports the emerging concept of prion-like propagation of abnormal proteins in noninfectious neurodegenerative diseases. Although the distance between involved regions is often considerable, the affected neurons are connected by axonal projections, indicating that physical contacts between nerve cells along axons are important for dissemination of ALS pathology. This article posits that the trajectory of the spreading pattern is consistent with the induction and dissemination of pTDP-43 pathology chiefly from cortical neuronal projections, via axonal transport, through synaptic contacts to the spinal cord and other regions of the brain.

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Figure 1: Sequential progression of pTDP-43 pathology in amyotrophic lateral sclerosis.
Figure 2: Corticofugal connections between regions of involvement in amyotrophic lateral sclerosis.
Figure 3: Putative mechanism of pTDP-43 propagation from cortical to subcortical neuronal projections.

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Acknowledgements

The authors' research was made possible by grants from the Wyncote Foundation, the Koller Family Foundation, NIH grants AG033101, AG017586, AG010124, AG032953, AG039510, and NS044266 (V. M. Lee, J. Q. Trojanowski), as well as the Deutsche Forschungsgemeinschaft grant number TR 1000/1-1 (H. Braak, K. Del Tredici). The authors thank D. Ewert (University of Ulm) for assistance with preparation of the original artwork.

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Authors and Affiliations

  1. Department of Neurology, Clinical Neuroanatomy Section, Centre for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, Ulm, 89081, Germany

    Heiko Braak & Kelly Del Tredici

  2. Department of Neurology, University of Ulm, Oberer Eselsberg 45, Ulm, 89081, Germany

    Johannes Brettschneider & Albert C. Ludolph

  3. Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, 19104, PA, USA

    Virginia M. Lee & John Q. Trojanowski

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H. Braak researched the data for the article. All authors made substantial contribution to discussion of the article content, to writing of the article, and to review and/or editing of the manuscript prior to submission.

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Correspondence to Heiko Braak.

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Supplementary information

Supplementary Table 1

Main types of nerve cells susceptible to development of pTDP-43 pathology in ALS (DOC 34 kb)

Supplementary Table 2

Neuronal types that develop no or very mild pTDP-43 pathology in ALS (DOC 30 kb)

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Braak, H., Brettschneider, J., Ludolph, A. et al. Amyotrophic lateral sclerosis—a model of corticofugal axonal spread. Nat Rev Neurol 9, 708–714 (2013). https://doi.org/10.1038/nrneurol.2013.221

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