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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.

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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
Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
Department of Biology, Georgetown University, Washington, DC 20057, USA.


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.


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

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