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

ABSTRACT

TTR (transthyretin) strikes a neuroprotective function in the prevention of amyloid-ß (Aß) 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 Aß amyloid-ß; 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.