PMID- 38019930 OWN - NLM STAT- MEDLINE DCOM- 20231204 LR - 20231215 IS - 1946-6242 (Electronic) IS - 1946-6234 (Linking) VI - 15 IP - 724 DP - 2023 Nov 29 TI - Enhanced mTORC1 signaling and protein synthesis in pathologic alpha-synuclein cellular and animal models of Parkinson's disease. PG - eadd0499 LID - 10.1126/scitranslmed.add0499 [doi] AB - Pathologic alpha-synuclein plays an important role in the pathogenesis of alpha-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be central to pathologic alpha-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic alpha-synuclein interactome. We report that the highest biological processes that interacted with pathologic alpha-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic alpha-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the alpha-synuclein preformed fibril mouse model and Drosophila transgenic models of pathologic alpha-synuclein-induced degeneration. Pathologic alpha-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in alpha-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic alpha-synuclein in cellular and animal models of PD. FAU - Khan, Mohammed Repon AU - Khan MR AUID- ORCID: 0000-0002-9744-9220 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Yin, Xiling AU - Yin X AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Kang, Sung-Ung AU - Kang SU AUID- ORCID: 0000-0002-8393-2588 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Mitra, Jaba AU - Mitra J AUID- ORCID: 0000-0001-6569-6203 AD - Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Wang, Hu AU - Wang H AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Ryu, Taekyung AU - Ryu T AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Brahmachari, Saurav AU - Brahmachari S AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Karuppagounder, Senthilkumar S AU - Karuppagounder SS AUID- ORCID: 0000-0002-3281-9913 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. FAU - Kimura, Yasuyoshi AU - Kimura Y AUID- ORCID: 0000-0001-9147-8058 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Jhaldiyal, Aanishaa AU - Jhaldiyal A AUID- ORCID: 0000-0002-0620-7390 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Kim, Hyun Hee AU - Kim HH AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Gu, Hao AU - Gu H AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Chen, Rong AU - Chen R AUID- ORCID: 0000-0001-9291-5539 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Redding-Ochoa, Javier AU - Redding-Ochoa J AUID- ORCID: 0000-0002-0677-917X AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Troncoso, Juan AU - Troncoso J AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Na, Chan Hyun AU - Na CH AUID- ORCID: 0000-0002-3622-2938 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Ha, Taekjip AU - Ha T AUID- ORCID: 0000-0003-2195-6258 AD - Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Howard Hughes Medical Institute, Baltimore, MD 21205, USA. FAU - Dawson, Valina L AU - Dawson VL AUID- ORCID: 0000-0002-2915-3970 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. AD - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Dawson, Ted M AU - Dawson TM AUID- ORCID: 0000-0002-6459-0893 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. AD - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. AD - Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. LA - eng PT - Journal Article DEP - 20231129 PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (alpha-Synuclein) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Snca protein, mouse) RN - Tuberous Sclerosis 2 SB - IM MH - Animals MH - Mice MH - alpha-Synuclein/metabolism MH - Disease Models, Animal MH - Mammals/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - *Parkinson Disease/metabolism MH - Proteomics MH - TOR Serine-Threonine Kinases EDAT- 2023/11/29 18:42 MHDA- 2023/12/01 06:44 CRDT- 2023/11/29 14:03 PHST- 2023/12/01 06:44 [medline] PHST- 2023/11/29 18:42 [pubmed] PHST- 2023/11/29 14:03 [entrez] AID - 10.1126/scitranslmed.add0499 [doi] PST - ppublish SO - Sci Transl Med. 2023 Nov 29;15(724):eadd0499. doi: 10.1126/scitranslmed.add0499. Epub 2023 Nov 29.