title: Metabolism and mis-metabolism of the neuropathological signature protein TDP-43.
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.
authors.affiliation: 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.
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Jayarama Krishnan
authors.initials: JK
authors.lastname: Bose
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Pritha
authors.initials: P
authors.lastname: Majumder
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Kuen-Haur
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Jen-Tse Joseph
authors.initials: JT
authors.lastname: Huang
authors.affiliation: Department of Biology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Che-Kun James
authors.initials: CK
authors.lastname: Shen
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins
keywords: Chaperone-mediated autophagy; Protein degradation; Proteolytic cleavage; TDP-43; TDP-43 proteinopathies; TDP-43-positive aggregate