title: Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC).
abstract: Many biological processes involve the mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Thus, the challenge of deciphering mTORC1-mediated functions during normal and pathological states in the central nervous system is challenging. Because mTORC1 is at the core of translation, we have investigated mTORC1 function in global and regional protein expression. Activation of mTORC1 has been generally regarded to promote translation. Few but recent works have shown that suppression of mTORC1 can also promote local protein synthesis. Moreover, excessive mTORC1 activation during diseased states represses basal and activity-induced protein synthesis. To determine the role of mTORC1 activation in protein expression, we have used an unbiased, large-scale proteomic approach. We provide evidence that a brief repression of mTORC1 activity in vivo by rapamycin has little effect globally, yet leads to a significant remodeling of synaptic proteins, in particular those proteins that reside in the postsynaptic density. We have also found that curtailing the activity of mTORC1 bidirectionally alters the expression of proteins associated with epilepsy, Alzheimer's disease, and autism spectrum disorder-neurological disorders that exhibit elevated mTORC1 activity. Through a protein-protein interaction network analysis, we have identified common proteins shared among these mTORC1-related diseases. One such protein is Parkinson protein 7, which has been implicated in Parkinson's disease, yet not associated with epilepsy, Alzheimers disease, or autism spectrum disorder. To verify our finding, we provide evidence that the protein expression of Parkinson protein 7, including new protein synthesis, is sensitive to mTORC1 inhibition. Using a mouse model of tuberous sclerosis complex, a disease that displays both epilepsy and autism spectrum disorder phenotypes and has overactive mTORC1 signaling, we show that Parkinson protein 7 protein is elevated in the dendrites and colocalizes with the postsynaptic marker postsynaptic density-95. Our work offers a comprehensive view of mTORC1 and its role in regulating regional protein expression in normal and diseased states.
authors.affiliation: From the ‡Center for Learning and Memory, University of Texas, Austin, 1 University Station C7000, Texas 78712; §Institute for Cell and Molecular Biology, University of Texas, Austin, Texas; ¶Institute for Neuroscience, University of Texas, Austin, Texas; ‖Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, Texas;
authors.forename: Farr
authors.initials: F
authors.lastname: Niere
authors.affiliation: From the ‡Center for Learning and Memory, University of Texas, Austin, 1 University Station C7000, Texas 78712; §Institute for Cell and Molecular Biology, University of Texas, Austin, Texas;
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Namjoshi
authors.affiliation: **Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409;
authors.forename: Ehwang
authors.initials: E
authors.lastname: Song
authors.affiliation: From the ‡Center for Learning and Memory, University of Texas, Austin, 1 University Station C7000, Texas 78712; §Institute for Cell and Molecular Biology, University of Texas, Austin, Texas; ¶Institute for Neuroscience, University of Texas, Austin, Texas;
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Dilly
authors.affiliation: ‡‡Pain Therapeutics, Inc., 7801 N Capital of Texas Hwy, #260, Austin, Texas 78731.
authors.forename: Grant
authors.initials: G
authors.lastname: Schoenhard
authors.affiliation: From the ‡Center for Learning and Memory, University of Texas, Austin, 1 University Station C7000, Texas 78712; §Institute for Cell and Molecular Biology, University of Texas, Austin, Texas; ¶Institute for Neuroscience, University of Texas, Austin, Texas;
authors.forename: Boris V
authors.initials: BV
authors.lastname: Zemelman
authors.affiliation: **Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409;
authors.forename: Yehia
authors.initials: Y
authors.lastname: Mechref
authors.affiliation: From the ‡Center for Learning and Memory, University of Texas, Austin, 1 University Station C7000, Texas 78712; §Institute for Cell and Molecular Biology, University of Texas, Austin, Texas; ¶Institute for Neuroscience, University of Texas, Austin, Texas; ‖Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, Texas; ‡‡Pain Therapeutics, Inc., 7801 N Capital of Texas Hwy, #260, Austin, Texas 78731 kimberly@mail.clm.utexas.edu.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Raab-Graham
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics*; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D054464:Peroxiredoxins / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000473:pathology
chemical_list: D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1