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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

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Abstract

Skein-like and spherical inclusions within the somatodendritic compartment of a few types of susceptible neurons in the human nervous system are the currently acknowledged pathological hallmarks of amyotrophic lateral sclerosis (ALS). These inclusions consist chiefly of an aggregated, phosphorylated, and ultimately ubiquitinated intranuclear protein, TDP-43. To investigate the development of these inclusions, a single neuronal type that is susceptible to the ALS-associated pathological process, i.e., the class of large multipolar somatomotor neurons in the lower brainstem and spinal cord, was studied in four cases of sporadic ALS and four age-matched controls using immunoreactions against phosphorylated TDP-43 (pTDP-43), p62, and ubiquitin. In these neurons, the protein TDP-43, after its displacement outside of the cell nucleus and abnormal phosphorylation, forms light microscopically visible dash-like aggregates which were dispersed throughout their entire somatodendritic domain and even extended into the proximal portions of the axon. Many motor neurons contained these lesions, which were not detectable with anti-TDP-43 and anti-p62. In an additional step, a small number of the neurons that contain the dash-like lesions displayed a clustering of the aggregated material, which forms thick net-like (potential precursors of the skein-like inclusions) and spherical inclusions. This material, in turn, was ubiquitinated and p62-immunopositive. Thus, dash-like pTDP-43 aggregates are regularly seen in motor neurons in ALS and may represent the initial cellular lesion in this disease. Because these aggregates were not stained with antibodies against p62 and non-phosphorylated TDP-43, it is possible that phosphorylation of TDP-43 is required for its aggregation in sporadic ALS.

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Acknowledgments

This study was made possible in part by funding from the German Research Council (Deutsche Forschungsgemeinschaft). They also wish to thank Ms. Corinna Hendrich, M.D. (Department of Neurology, University of Ulm) for help with clinical protocols, as well as Ms. Siegrid Baumann, Ms. Gabrielle Ehmke, Ms. Verena Hofmann, Ms. Irina Lungrin (immunohistochemistry), and Mr. Stephan Mayer (graphics) for their technical expertise.

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Authors and Affiliations

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

    Heiko Braak, Albert Ludolph, Dietmar R. Thal & Kelly Del Tredici

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  1. Heiko Braak
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  2. Albert Ludolph
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  3. Dietmar R. Thal
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  4. Kelly Del Tredici
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Correspondence to Heiko Braak.

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Braak, H., Ludolph, A., Thal, D.R. et al. 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, 67–74 (2010). https://doi.org/10.1007/s00401-010-0683-0

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  • DOI: https://doi.org/10.1007/s00401-010-0683-0

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