TDP ‐43 loss of function increases TFEB activity and blocks autophagosome–lysosome fusion

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by selective loss of motor neurons in brain and spinal cord. TAR DNA-binding protein 43 (TDP-43) was identified as a major component of disease pathogenesis in ALS, frontotemporal lobar degeneration (FTLD), and other neurodegenerative disease. Despite the fact that TDP-43 is a multi-functional protein involved in RNA processing and a large number of TDP-43 RNA targets have been discovered, the initial toxic effect and the pathogenic mechanism underlying TDP-43-linked neurodegeneration remain elusive. In this study, we found that loss of TDP-43 strongly induced a nuclear translocation of TFEB, the master regulator of lysosomal biogenesis and autophagy, through targeting the mTORC1 key component raptor. This regulation in turn enhanced global gene expressions in the autophagy-lysosome pathway (ALP) and increased autophagosomal and lysosomal biogenesis. However, loss of TDP-43 also impaired the fusion of autophagosomes with lysosomes through dynactin 1 downregulation, leading to accumulation of immature autophagic vesicles and overwhelmed ALP function. Importantly, inhibition of mTORC1 signaling by rapamycin treatment aggravated the neurodegenerative phenotype in a TDP-43-depleted Drosophila model, whereas activation of mTORC1 signaling by PA treatment ameliorated the neurodegenerative phenotype. Taken together, our data indicate that impaired mTORC1 signaling and influenced ALP may contribute to TDP-43-mediated neurodegeneration.

DCTN1-related neurodegeneration: Perry syndrome and beyond

“…Xia et al showed that a loss of TDP-43 decreased the expression of DCTN1, leading to the inhibition of autophagosome-lysosome fusion in TDP-43-depleted cells. As a result, the accumulation of autophagic cargo induced neurotoxicity [67]. The loss of function of the DCTN1 protein might result in such a vicious cycle in affected cells and contribute to TDP-43 accumulation.…”

Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72

“…In this study authors also reported that TDP-43 controls the level of RAPTOR, which is required to maintain the activity of mTOR, by stabilizing its mRNA (Xia et al, 2016). Thus, silencing of TDP-43 inactivated mTOR by decreasing RAPTOR levels (Xia et al, 2016).…”

TDP-43 in the spectrum of MND-FTLD pathologies

“…The autophagosome then fuses with the lysosome, forming an autophagolysosome, where the contents are degraded by acidic enzymes (Monahan, Shewmaker, & Pandey, 2016). Aggregated forms of TDP-43 are degraded via autophagy (Xia, et al, 2016). …”

“…Autophagy has been shown to be dysfunctional in forms of ALS and caused by TARDBP mutations and it has been suggested that TDP-43 is involved in regulation of autophagy by affecting the biogenesis of autophagosomes and lysosomes (Filimonenko, et al, 2007; Bose, Huang, & Shen, 2011; Xia, et al, 2016; Ying, et al, 2016). Because of the importance of protein homeostasis in maintaining healthy neurons, a functional protein degradation system is highly important.…”