TARDBP/TDP-43 regulates autophagy in both MTORC1-dependent and MTORC1-independent manners. Issue 4 (2nd April 2016)

• Record Type: Journal Article
• Authors: Ying, Zheng; Xia, Qin; Hao, Zongbing; Xu, Delai; Wang, Mingmei; Wang, Hongfeng; Wang, Guanghui
• Is Part Of: Autophagy. Volume 12:Issue 4(2016)
• Page Start: 707
• Page End: 708
• Publication Date: 2016-04-02
• Subjects: Autophagy -- lysosome -- MTORC1 -- TDP-43 -- TFEB; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2016.1151596
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: 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.