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

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 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
Volume127
Issue number14
DOIs
Publication statusPublished - 2014

Fingerprint

TDP-43 Proteinopathies
Autophagy
Caspases
Frontotemporal Lobar Degeneration
Proteins
Amyotrophic Lateral Sclerosis
Proteasome Endopeptidase Complex
Ubiquitin
Neurodegenerative Diseases
Cultured Cells

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Huang, C. C., Bose, J. K., Majumder, P., Lee, K. H., Huang, J. T. J., Huang, J. K., & Shen, C. K. J. (2014). Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. Journal of Cell Science, 127(14), 3024-3038. https://doi.org/10.1242/jcs.136150

Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. / Huang, Chi Chen; Bose, Jayarama Krishnan; Majumder, Pritha; Lee, Kuen Haur; Huang, Jen Tse Joseph; Huang, Jeffrey K.; Shen, Che Kun James.

In: Journal of Cell Science, Vol. 127, No. 14, 2014, p. 3024-3038.

Research output: Contribution to journalArticle

Huang, CC, Bose, JK, Majumder, P, Lee, KH, Huang, JTJ, Huang, JK & Shen, CKJ 2014, 'Metabolism and mis-metabolism of the neuropathological signature protein TDP-43', Journal of Cell Science, vol. 127, no. 14, pp. 3024-3038. https://doi.org/10.1242/jcs.136150
Huang, Chi Chen ; Bose, Jayarama Krishnan ; Majumder, Pritha ; Lee, Kuen Haur ; Huang, Jen Tse Joseph ; Huang, Jeffrey K. ; Shen, Che Kun James. / Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. In: Journal of Cell Science. 2014 ; Vol. 127, No. 14. pp. 3024-3038.
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