Neuroprotective effects of reactive oxygen species mediated by BDNF-independent activation of TrkB
Yang Zhong Huang1, James O McNamara
1Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
Reactive oxygen species (ROS) have diverse biological consequences in the mammalian CNS, but the molecular targets mediating these pleiotropic effects are incompletely understood. Like ROS, the neurotrophin receptor, TrkB receptor tyrosine kinase, has diverse effects in the developing and mature mammalian brain. Our discovery that zinc can transactivate TrkB, together with the finding that ROS can trigger zinc release from cytosolic zinc binding proteins, led us to hypothesize that ROS can transactivate TrkB in CNS neurons by a zinc-dependent mechanism. We found that both exogenous H(2)O(2) and endogenous ROS activate TrkB signaling by a Src family kinase-dependent but brain-derived neurotrophic factor-independent mechanism in cultured rat cortical neurons. Exogenous H(2)O(2) enhances cytosolic zinc content in a metallothionein-3 (MT-3)-requiring manner. Both exogenous H(2)O(2) and endogenous ROS mediated transactivation of TrkB requires intracellular zinc and MT-3. The ROS-triggered transactivation of TrkB exerts neuroprotective effects, because inhibition of TrkB kinase activity or uncoupling Shc signaling from TrkB exacerbates neuronal cell death induced by H(2)O(2). Thus, we propose a molecular signaling event whereby ROS induce release of zinc from cytosolic MT-3, the increased cytosolic zinc transactivates TrkB, and the enhanced Shc signaling downstream from TrkB promotes prosurvival effects. We suggest that such neuroprotective effects mediated by ROS are operative in diverse acute and chronic neurological disorders.
Insights
Reactive oxygen species (ROS) activate TrkB signaling via zinc release from metallothionein-3 (MT-3), promoting neuroprotection. This pathway offers therapeutic potential for neurological disorders.
Area of Science:
- Neuroscience
- Cellular Signaling
- Oxidative Stress Biology
Background:
- Reactive oxygen species (ROS) have complex roles in the central nervous system (CNS), but their molecular targets are not fully understood.
- The neurotrophin receptor, TrkB, also plays critical roles in CNS development and function.
- Previous work showed zinc can activate TrkB, and ROS can release zinc.
Purpose of the Study:
- To investigate if ROS can activate TrkB in CNS neurons through a zinc-dependent mechanism.
- To elucidate the molecular pathway linking ROS, zinc, and TrkB signaling.
- To determine the neuroprotective role of ROS-induced TrkB activation.
Main Methods:
- Cultured rat cortical neurons were treated with hydrogen peroxide (H2O2) or other ROS.
- TrkB signaling activation was assessed.
- Intracellular zinc levels and the role of metallothionein-3 (MT-3) were examined.
- Neuroprotection was evaluated by inhibiting TrkB kinase or Shc signaling.
Main Results:
- Both exogenous and endogenous ROS activated TrkB signaling in a Src family kinase-dependent and BDNF-independent manner.
- ROS exposure increased cytosolic zinc in an MT-3-dependent way.
- ROS-mediated TrkB transactivation required intracellular zinc and MT-3.
- Inhibition of TrkB or Shc signaling worsened H2O2-induced neuronal death, indicating a neuroprotective role.
Conclusions:
- ROS trigger TrkB transactivation by releasing zinc from MT-3, leading to enhanced Shc signaling and neuroprotection.
- This ROS-zinc-TrkB pathway is a key mechanism for neuronal survival.
- The findings suggest potential therapeutic strategies for neurological disorders involving oxidative stress.
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