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

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 (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.

Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations

“… 198 Reduced levels of native transthyretin 76 and increased levels of oxidized CysGly–transthyretin are found in the CSF in ALS compared with controls 67 and may be involved in dealing with TDP-43 inclusions. 199 There are also several genetic mutations of transthyretin resulting in amyloid neuropathy that can mimic motor symptoms of ALS. 198 Like Cst C, it is not specific for ALS.…”

Early activation of cellular stress and death pathways caused by cytoplasmic TDP-43 in the rNLS8 mouse model of ALS and FTD

“…Moreover, in cell culture, disease-associated mutant TDP-43 proteins trigger ISR activation and elevation of downstream gene expression including Chop, involving an amplifying cell stress response potentially leading to cell death [15]. Indeed, future experiments are required to assess the effects of modulation of other ISR genes such as Atf4, which has broader downstream effects [11,12] and may be involved in the clearance of TDP-43 inclusions via autophagy [45]. Furthermore, CHOP was recently identified as one of the top upregulated genes in a human neuronal model of TDP-43 pathology, and was shown to be a direct target of TDP-43-mediated gene expression with increased CHOP levels in neurons with depleted nuclear TDP-43 in human FTLD-TDP-derived samples [46].…”