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

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 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). We found that TTR accumulates with TDP-43 cytoplasmic inclusions in FTLD-TDP human patients and transgenic mice, in which TTR exhibits dramatic expression decline in elderly mice. The upregulation of TTR expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, whereof TTR induces autophagy upregulation via ATF4. Of interest, TTR upregulated ATF4 expression and promoted ATF4 nuclear import, presenting physical interaction. Neuronal expression of TTR in FTLD-TDP mice restored autophagy function and facilitated early soluble TDP-43 aggregates for autophagosome targeting, ameliorating neuropathology and behavioral deficits. Thus, TTR conducted two-way regulations by either inducing autophagy activation or escorting TDP-43 aggregates targeted autophagosomes, suggesting that TTR is a potential modulator therapy for neurological disorders caused by TDP-43 proteinopathy.