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

Chi Chen Huang, Jayarama Krishnan Bose, Pritha Majumder, Kuen Haur Lee, Jen Tse Joseph Huang, Jeffrey K. Huang, Che Kun James Shen

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80 Citations (Scopus)


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 themetabolism 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 mismetabolism of TDP-43 in relation to these findings is presented.

Original languageEnglish
Pages (from-to)3024-3038
Number of pages15
JournalJournal of Cell Science
Issue number14
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Cell Biology


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