Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia
| Autor: | Yan Chen Shang, Zhao Zhong Chong, Kenneth Maiese, Shaohui Wang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Apoptosis Article Cell Line CCN Intercellular Signaling Proteins Mice Cellular and Molecular Neuroscience Developmental Neuroscience AMP-activated protein kinase Proto-Oncogene Proteins Tuberous Sclerosis Complex 2 Protein Animals Phosphorylation PI3K/AKT/mTOR pathway Membrane Potential Mitochondrial Amyloid beta-Peptides biology Tumor Suppressor Proteins Cytochromes c AMPK Cytoprotection Peptide Fragments Mitochondria Cell biology Tuberous sclerosis protein Neurology biology.protein Microglia TSC2 Signal transduction Signal Transduction |
| Zdroj: | Current Neurovascular Research. 10:29-38 |
| ISSN: | 1567-2026 |
| DOI: | 10.2174/156720213804806007 |
| Popis: | More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β.-amyloid (Aβ.) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser1387) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr1462) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ. exposure. |
| Databáze: | OpenAIRE |
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