Presented By: Jacob McPhail, PhD

Speaker Biography: Dr. Jacob A. McPhail is a biochemist with expertise in the structure, function, and regulation of protein complexes. He received his BSc (Hons) in Microbiology and PhD in Biochemistry from the University of Victoria in Canada. His dissertation work focused on the reconstitution of lipid kinases on membranes in vitro to study their regulation and roles in disease. Utilizing a multifaceted approach of hydrogen-deuterium exchange mass spectrometry, X-ray crystallography and cell biology, he explained several mechanisms by which RNA viruses hijack host lipid kinases during infection. Translationally, he aided in the discovery and development of dozens of novel anti-viral, anti-malarial and anti-cancer lipid kinase inhibitors. Dr. McPhail has since applied his biochemistry expertise to neurobiology, specifically investigating the key protein aggregates present in Alzheimer’s and Parkinson’s diseases. He is currently generating and characterizing pathogenic protein oligomers and fibrils in vitro to develop these as novel molecular tools to accelerate neurodegenerative disease research.

Webinar: Novel Tools for Drug Discovery in Neurodegenerative Diseases

Webinar Abstract: Alzheimer’s and Parkinson’s diseases (AD, PD) are the two most common neurodegenerative disorders. Both diseases are characterized by abnormal aggregates in the brain, which include alpha-synuclein, tau and amyloid beta (Aβ). These proteins share a common pathological mechanism whereby aggregation leads to neuronal toxicity and plaque formation. A key goal in advancing AD/PD drug discovery is establishing disease models that effectively mimic pathology observed in vivo. We have developed consistent, scalable methods to generate active neurotoxic protein aggregates in vitro. Recently we generated fibrils of pyroglutamate Aβ, an N-terminally truncated peptide modified by glutaminyl cyclase present in late-stage AD, and fibrils of the tau dGAE fragment, which we show more closely demonstrates AD-like fibril pathology than other tau fibrils. Finally, we have also generated co-polymer alpha-synuclein and tau fibrils. These novel molecular tools expand the range of constructs available to study neurodegenrative disease and facilitate AD/PD drug discovery efforts.

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