TARDBP/TDP-43 regulates autophagy in both MTORC1-dependent and MTORC1-independent manners

• Published in: Autophagy Vol. 12; no. 4; pp. 707 - 708
• Main Authors: Ying, Zheng, Xia, Qin, Hao, Zongbing, Xu, Delai, Wang, Mingmei, Wang, Hongfeng, Wang, Guanghui
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.04.2016
• Subjects: Animals; Autophagic Puncta; Autophagy; DNA-Binding Proteins - metabolism; Humans; lysosome; Lysosomes - metabolism; Mechanistic Target of Rapamycin Complex 1; MTORC1; Multiprotein Complexes - metabolism; Phagosomes - metabolism; Signal Transduction; TDP-43; TFEB; TOR Serine-Threonine Kinases - metabolism; TFEB; MTORC1; Autophagy; lysosome; TDP-43
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2016.1151596

In a recent paper we addressed the mechanism by which defective autophagy contributes to TARDBP/TDP-43-mediated neurodegenerative disorders. We demonstrated that TARDBP regulates MTORC1-TFEB signaling by targeting RPTOR/raptor, a key component and an adaptor protein of MTORC1. Loss of TARDBP decreased the mRNA stability of RPTOR and this regulation in turn enhanced autophagosomal and lysosomal biogenesis in an MTORC1-dependent manner. Meanwhile, loss of TARDBP could also impair autophagosome-lysosome fusion in an MTORC1-independent manner. Importantly, we found that modulation of MTOR activity by treatment with rapamycin and phosphatidic acid had strong effects on the neurodegenerative phenotypes of TBPH (Drosophila TARDBP)-depleted flies. Taken together, our data reveal that multiple dysfunctions in the autophagic process contribute to TARDBP-linked neurodegeneration and may help to identify potential therapeutic targets in the future.