BCAT-induced autophagy regulates Aβ load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer's disease

Harris, M.; El Hindy, M.; Usmari-Moraes, Marcela; Hudd, Fred; Shafei, Mai; Dong, M.; Hezwani, M.; Clark, P.; House, M.; Forshaw, T.; Kehoe, P.; Conway, Myra E.

Abstract

Leucine, nutrient signal and substrate for the branched chain aminotransferase (BCAT) activates the mechanistic target of rapamycin (mTORC1) and regulates autophagic flux, mechanisms implicated in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease (AD). BCAT is upregulated in AD, where a moonlighting role, imparted through its redox-active CXXC motif, has been suggested. Here we demonstrate that the redox state of BCAT signals differential phosphorylation by protein kinase C (PKC) regulating the trafficking of cellular pools of BCAT. We show inter-dependence of BCAT expression and proteins associated with the P13K/Akt/mTORC1 and autophagy signalling pathways. In response to insulin or an increase in ROS, BCATc is trafficked to the membrane and docks via palmitoylation, which is associated with BCATc-induced autophagy through PKC phosphorylation. In response to increased levels of BCATc, as observed in AD, amyloid β (Aβ) levels accumulate due to a shift in autophagic flux. This effect was diminished when incubated with leucine, indicating that dietary levels of amino acids show promise in regulating Aβ load. Together these findings show that increased BCATc expression, reported in human AD brain, will affect autophagy and Aβ load through the interdependence of its redox-regulated phosphorylation offering a novel target to address AD pathology.

• Journal Article Type: Article
• Acceptance Date: Jan 16, 2020
• Online Publication Date: Jan 23, 2020
• Deposit Date: Feb 7, 2020
• Publicly Available Date: Jan 24, 2021
• Journal: Free Radical Biology and Medicine
• Print ISSN: 0891-5849
• Electronic ISSN: 1873-4596
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1016/j.freeradbiomed.2020.01.019
• Keywords: BCAT, phosphorylation, redox regulated, PKC, insulin signalling, autophagy, Aβ
• Public URL: https://uwe-repository.worktribe.com/output/5332577
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S089158491932564X