Doctor Myeku’s lab has a long-standing interest in understanding the mechanism of deficient protein quality control in tauopathy disorders that have a common feature – accumulation of pathological tau. In particular, we are interested in studying the ubiquitin proteasome system (UPS), which is the principal pathway for protein turnover in mammalian cells. Degradation of proteins via the UPS involves two discrete and successive steps: tagging of the substrate protein covalently by poly-ubiquitin chain and the subsequent degradation of the tagged protein by the 26S proteasome, composed of the 20S catalytic core and the19S regulatory particle. As we age the function of 26S proteasomes in neurons become less efficient, but in Alzheimer’s disease and many neurodegenerative diseases, proteasome function becomes profoundly impaired contributing to accumulation of oligomers and aggregates, which is a common pathological hallmark of these, otherwise clinically and etiologically diverse diseases. We are using unique transgenic mouse models of 26S proteasome and tauopathy to identify mechanisms associated with dysregulated clearance of tau and disease progression.
Another major focus of our research is translating our knowledge of the UPS biology into novel therapeutic approaches for treatment of Alzheimer’s disease and possibly other proteotoxic diseases. Our lab has demonstrated that phosphorylation of 26S proteasomes, by clinically relevant drugs, can lead to activated proteasome proteolysis, resulting in decreased insoluble tau levels, attenuated tauopathy and rescued cognitive performance (Myeku et al. 2016). And current in vivo projects are underway to identify pathways for on-target, locally restricted proteasome activation in neurons where misfolded proteins accumulate first in early stages of Alzheimer’s disease. My overarching goal is to continue my research to understanding proteinopathy-induced diseases and their relationship with protein quality control in the cell. Utilizing my current expertise in clearance machinery, transgenic mouse models and with a background in translational research, I plan to fully devote my career to translational science, where new discoveries can hopefully be translated swiftly into new therapies for neurodegenerative diseases, many of which are currently incurable.