Effects of Oxidative Stress on Microtubules and its Role in Tauopathic Disease

Grant Winners

  • Travis Craddock, Ph.D. – College of Psychology
  • Mary Jeffrey, M.S. – College of Psychology

Dean

  • Karen Grosby, Ed.D. – College of Psychology

Abstract

Oxidative stress is a pathological hallmark of tauopathic disorders; diseases that can change the microtubule associated protein tau (MAPT) into forms that disrupt nerve impulses, including Alzheimer’s disease, fronto-temporal lobar degeneration, and Parkinson's disease associated dementia.  MAPT is a key protein in stabilizing the microtubule architecture that regulates neuron morphology and synaptic strength, and which degrades in tauopathic disorders. The precise role of reactive oxygen species (ROS) in the tauopathic disease process however is poorly understood. Classically, mitochondria have been viewed as the major source for oxidative stress. It has been shown that the production of ROS by mitochondria can result in spontaneous ultra-weak photon emission within cells.  While of low intensity, surrounding proteins within the cytosol can still absorb these high-energy photons via aromatic amino acids (tryptophan, tyrosine, phenylalanine).  The most likely absorbers of these photons is the microtubule cytoskeleton, as it forms a vast network spanning neurons, is highly co-localized with mitochondria, and shows a high density of aromatic amino acids.  Functional microtubule networks may respond to this ROS generated endogenous photon energy as a form of intracellular signaling, or may serve as a dissipater of such energy to protect the cell from potentially harmful effects. Experimentally, after exposure to exogenous photons microtubules have been shown to reorient/reorganize in a dose-dependent manner, with the greatest effect being observed around 280 nm, in the tryptophan absorption range.

Our recent modeling efforts based on ambient temperature experiment have shown that microtubules can feasibly absorb and funnel this type of energy.  Since microtubule networks are compromised in cognitively impaired tauopathic diseases, patients with these illnesses would be unable to support effective channeling of these photons for signaling/dissipation, and consequent emission surplus due to increased production of ROS, or decreased ability to absorb and transfer, may lead to cellular oxidative damage and hasten the degenerative process.  Here we propose to perform temperature dependent spectroscopy to measure the absorption characteristics of the microtubule constituent protein tubulin and further refine our model of the effect of oxidative stress on the microtubule cytoskeleton.  Outcomes from this study can lead to practical and effective strategies to delay neurodegenerative decline in populations at most risk, and can prevent or attenuate the physical, psychological, and economic burden associated with tauopathic illness.