Microtubule Regulating Pathways in Synaptic Injury and Bortezomib-Induced Axonal Degeneration
Emerging studies from several groups have indicated that dynamic microtubules, in addition to modified microtubules, play key roles in neuronal function. In addition, synaptic biphasic fluctuations of microtubule instability/stability and tubulin post-translational modifications (PTMs) have recently been associated with memory formation and are disrupted in aging, indicating a primary role for the regulation of microtubule dynamics and tubulin PTMs in the maintenance of synaptic plasticity. In support of this model, we recently found that stabilization of dynamic microtubules and induction of tubulin PTMs by the formin mDia1 contribute to oligomeric Aβ1-42 synaptotoxicity, and inhibition of microtubule dynamics alone is sufficient to promote tau hyperphosphorylation and tau dependent synaptotoxicity (Qu et al., J Cell Biol, 2017). To test whether these changes occur at synapses and are directly responsible for synapse loss, we have further developed microscopy assays that measure microtubule invasions into dendritic spines and microtubule contacts with single presynaptic boutons of hippocampal and cortical neurons in culture. We are currently using these assays to investigate the temporal and spatial nature of these changes in the intact synapse upon modulation of synaptic activity or synaptic injury. These exciting findings are in line with a parallel study in which we are testing whether undesired fluctuations in tubulin PTMs are primary to axonal neurodegeneration induced by chemotherapeutic agents in sensory neurons using in vitro and in vivo models of disease. Altogether, our ongoing studies introduce a novel activity for dynamic microtubules in neuronal injury, and demonstrate an unforeseen role for dynamic microtubule behavior and tubulin PTMs in regulating tau phosphorylation, synaptic function and axonal integrity.
Columbia University, New York, USA
Domain 1 - UMR 3348 - Genotoxic Stress and Cancer