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J Cell Sci. 2014 Jul 15;127(Pt 14):3024-38. doi: 10.1242/jcs.136150. Epub 2014 May 23.

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43.

Author information

1
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology/Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan hcc0609@tmu.edu.tw ckshen@imb.sinica.edu.tw.
2
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
3
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
4
Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
5
Department of Biology, Georgetown University, Washington, DC 20057, USA.

Abstract

TDP-43 (also known as TARDBP) is a pathological signature protein of neurodegenerative diseases, with TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD)-TDP and amyotrophic lateral sclerosis (ALS)-TDP. These TDP-43 proteinopathies are characterized by cytoplasmic insoluble TDP-43-positive aggregates in the diseased cells, the formation of which requires the seeding of TDP-25 fragment generated by caspase cleavage of TDP-43. We have investigated the metabolism and mis-metabolism of TDP-43 in cultured cells and found that endogenous and exogenously overexpressed TDP-43 is degraded not only by the ubiquitin proteasome system (UPS) and macroautophagy, but also by the chaperone-mediated autophagy (CMA) mediated through an interaction between Hsc70 (also known as HSPA8) and ubiquitylated TDP-43. Furthermore, proteolytic cleavage of TDP-43 by caspase(s) is a necessary intermediate step for degradation of the majority of the TDP-43 protein, with the TDP-25 and TDP-35 fragments being the main substrates. Finally, we have determined the threshold level of the TDP-25 fragment that is necessary for formation of the cytosolic TDP-43-positive aggregates in cells containing the full-length TDP-43 at an elevated level close to that found in patients with TDP-43 proteinopathies. A comprehensive model of the metabolism and mis-metabolism of TDP-43 in relation to these findings is presented.

KEYWORDS:

Chaperone-mediated autophagy; Protein degradation; Proteolytic cleavage; TDP-43; TDP-43 proteinopathies; TDP-43-positive aggregate

PMID:
24860144
DOI:
10.1242/jcs.136150
[Indexed for MEDLINE]
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