title: Wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern β-amyloid apoptotic injury of microglia.
abstract: Given the present challenges to attain effective treatment for β-amyloid (Aβ) toxicity in neurodegenerative disorders such as Alzheimer's disease, development of novel cytoprotective pathways that can assist immune mediated therapies through the preservation of central nervous system microglia could offer significant promise. We show that the CCN4 protein, Wnt1 inducible signaling pathway protein 1 (WISP1), is initially up-regulated by Aβ and can modulate its endogenous expression for the protection of microglia during Aβ mediated apoptosis. WISP1 activates mTOR and phosphorylates p70S6K and 4EBP1 through the control of the regulatory mTOR component PRAS40. Loss of PRAS40 through gene reduction or inhibition by WISP1 is cytoprotective. WISP1 ultimately governs PRAS40 by sequestering PRAS40 intracellularly through post-translational phosphorylation and binding to protein 14-3-3. Our work identifies WISP1, mTOR signaling, and PRAS40 as targets for new strategies directed against Alzheimer's disease and related disorders.
authors.affiliation: Laboratory of Cellular and Molecular Signaling, Cancer Center, F 1220, New Jersey Health Sciences University, 205 South Orange Avenue, Newark, NJ 07101, USA.
authors.forename: Yan Chen
authors.initials: YC
authors.lastname: Shang
authors.forename: Zhao Zhong
authors.initials: ZZ
authors.lastname: Chong
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Maiese
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology*; D055511:CCN Intercellular Signaling Proteins / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D011897:Random Allocation; D015854:Up-Regulation / Q000502:physiology
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D011518:Proto-Oncogene Proteins