Time: 16:00 - 17:30, Thursday, December 7, 2017

Venue: D326, Medicial Science Building, Tsinghua University

Speaker：Professor Yang Hu

Host: Dr. Yichang Jia, PI of Tsinghua McGovern

Title: Neuronal Intrinsic Signaling for Neuroprotection and Axon Regeneration

Abstract：

Axonopathy is a typical early characteristic of neurodegenerative diseases in central nervous system (CNS), which leads to axon degeneration and retrograde neuronal cell death. It is critical to decipher the upstream signals that trigger the neurodegeneration cascade to minimize the severe consequences of progressive CNS dysfunction. Optic neuropathies are a group of retinal ganglion cell (RGC) diseases with features of axonopathy: they are initiated by optic nerve (ON) injury and that produces secondary RGC death. Our studies of three in vivo mouse models of optic neuropathies (traumatic ON injury, glaucoma and EAE/optic neuritis) revealed that both acute traumatic injury and chronic insult of ON induce endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) signal transduction pathways in RGCs. Modulation of two key downstream pathways of ER stress synergistically promote survival of both RGC somata and axons in all three optic neuropathy models, suggest that neuronal ER stress is a general upstream mechanism for both events in CNS axonopathies, and that axon injury-induced ER stress is the link between the sequential events of axon injury and neuronal soma death.

It is also upmost interest to promote CNS axon regeneration for neural repair. Deletion of phosphatase and tensin homolog (PTEN), the negative regulator of phosphatidylinositol 3-kinase (PI3K), induces RGC axon/ON regeneration. AKT is the major effector of the PI3K pathway; it is phosphorylated by PDK1 and mTOR complex 2 (mTORC2) at two different amino acids, T308 and S473, respectively. AKT is also the upstream regulator of mTOR complex 1 (mTORC1) and GSK3β. Here we molecularly dissect this complicated pathway and elucidate how AKT coordinates the signaling of these two mTOR complexes and GSK3β in adult mouse RGCs to influence ON regeneration in vivo. Our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.