CAREER: Oligomeric Stoichiometry of Superoxide Dismutase 1 and Neuronal Antioxidant Defense

High levels of metabolic activity require neurons to be competent in handling oxidative stress. This project seeks to understand how neurons modulate the assembly of Cu/Zn superoxide dismutase (SOD1), the frontline antioxidant protein, when they encounter environmental oxidative reagents. The results of this project will inform how oxidative stress changes SOD1 structures for neuronal antioxidant defense. In addition, the PI will initiate a new educational program, 'Quantitative Biophysical Comprehension' (QBiC), to teach students how to quantify the structural state of a protein using bio-imaging experiments. QBiC will provide interdisciplinary training, modernize the chemistry curriculum and contribute to the NSF goal of developing a strong STEM workforce. Modulation of SOD1 oligomeric states plays a critical role in its function and is thus essential to neuronal antioxidant defense; however, its molecular mechanisms are poorly understood due to the lack of proper analytical tools to quantify protein oligomerization in cells. In the first part of this research program, the PI will develop a quantitative single-molecule approach to quantify SOD1 oligomerizations in the nucleus, cytosol, and mitochondria. An in-cell redox sensor will be employed to quantify the subcellular oxidative status, and mass spectrometry will be used to quantify changes in SOD1 posttranslational modifications under various environmental stressors. The success of this work will answer for the first time how SOD1 interactions and oligomeric distribution are finely tuned in neurons in response to environmental stimuli. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.