Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP

Yuan Ping Chu, Lee Way Jin, Liang Chao Wang, Pei Chuan Ho, Wei Yen Wei, Kuen Jer Tsai

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4. Of interest, transthyretin upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of transthyretin in frontal temporal lobar degeneration-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioural deficits. Thus, transthyretin conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that transthyretin is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.

Original languageEnglish
Pages (from-to)2089-2106
Number of pages18
JournalBrain
Volume146
Issue number5
DOIs
Publication statusPublished - 2023 May 1

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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