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Cell Rep. 2013 Jul 11;4(1):124-34. doi: 10.1016/j.celrep.2013.06.007. Epub 2013 Jul 3.

Prion-like properties of pathological TDP-43 aggregates from diseased brains.

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  • 1Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan. nonaka-tk@igakuken.or.jp

Abstract

TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
23831027
[PubMed - indexed for MEDLINE]
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