TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy

Yuan-Ping Chu; Pei-Chuan Ho; Kuen-Jer Tsai

doi:10.1080/15548627.2023.2167690

TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy

Autophagy. 2023 Aug;19(8):2403-2405. doi: 10.1080/15548627.2023.2167690. Epub 2023 Jan 18.

Authors

Yuan-Ping Chu¹, Pei-Chuan Ho¹, Kuen-Jer Tsai^{1

2}

Affiliations

¹ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Abstract

TTR (transthyretin) strikes a neuroprotective function in the prevention of amyloid-β (Aβ) deposition in Alzheimer disease (AD). Perturbation of the stringently controlled TARDBP/TDP-43 (TAR DNA binding protein) expression gives rise to cytoplasmic aggregation, characterized by TARDBP proteinopathy affiliated with several neurological disorders, including frontotemporal lobar degeneration with TARDBP pathology (FTLD-TDP) and amyotrophic lateral sclerosis/ALS. Proposedly, TTR can maintain cellular proteostasis susceptible to TARDBP aggregates and initiate its removal. Herein, we disclose that TTR upregulated in response to excessive TARDBP causes TARDBP aggregation in FTLD-TDP and co-accumulates with it. Moreover, TTR expression increases with age in FTLD-TDP but shows a downward decline in the elderly. TTR promotes macroautophagy/autophagy activity and facilitates aggregated TARDBP degradation via autophagy. Compellingly, TTR binds to ATF4 and boosts its nuclear import for autophagy upregulation. Therefore, TTR directs autophagy teamwork in bi-directional regulation through enhancing autophagy activity via ATF4 and chaperoning aggregated TARDBP to phagophores for degradation.Abbreviations: Aβ: amyloid-β; AD: Alzheimer disease; ER: endoplasmic reticulum; FTLD-TDP: frontotemporal lobar degeneration with TARDBP pathology; TARDBP/TDP-43: TAR DNA binding protein; TTR: transthyretin; UPR: unfolded protein response.

Keywords: ATF4; FTLD; TDP-43; TTR; autophagy; proteinopathy.

Publication types

Research Support, Non-U.S. Gov't
Comment

MeSH terms

Aged
Alzheimer Disease*
Amyotrophic Lateral Sclerosis* / metabolism
Autophagy
DNA-Binding Proteins / metabolism
Frontotemporal Dementia*
Frontotemporal Lobar Degeneration* / metabolism
Humans
Prealbumin
TDP-43 Proteinopathies*

Substances

Prealbumin
DNA-Binding Proteins

Grants and funding

This study was performed, in part, with support from the National Science and Technology Council, Taiwan (MOST-106-2628-B-006-001-MY4, NSTC-111-2320-B-006-038-MY3), and National Cheng Kung University Hospital.