title: TARDBP/TDP-43 regulates autophagy in both MTORC1-dependent and MTORC1-independent manners.
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.
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.|b Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ying
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xia
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Zongbing
authors.initials: Z
authors.lastname: Hao
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Delai
authors.initials: D
authors.lastname: Xu
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Mingmei
authors.initials: M
authors.lastname: Wang
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou , Jiangsu , China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; MTORC1; TDP-43; TFEB; lysosome