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

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.

Source: EMBO Journal - January 17, 2016 Category: Molecular Biology Authors: Xia, Q., Wang, H., Hao, Z., Fu, C., Hu, Q., Gao, F., Ren, H., Chen, D., Han, J., Ying, Z., Wang, G. Tags: Autophagy & Cell Death, Neuroscience, RNA Biology Articles Source Type: research