Friday, November 3, 2023

Protein misfolding and amyloid disaggregases to counter misfolding

12:00 PM

BSRB, Room 5515 and
Virtual via Zoom

Neurology/Neuroscience Research Seminar

Scan the QR code to register your attendance for CME credit.

Protein misfolding underpins numerous fatal neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD). Disaggregases are proteins that can engage misfolded proteins and amyloid fibrils and solubilize them, promoting their return to fold and function or allowing their degradation. Hsp104 is an AAA+ protein disaggregase from yeast. While Hsp104 solubilizes disordered aggregates and amyloid in yeast, it has only limited activity against human neurodegenerative disease-associated proteins. However, we have demonstrated that Hsp104 can be reprogrammed to reverse the misfolding and suppress the toxicity of several disease-associated aggregation-prone proteins. However, these variants can have off-target effects due suboptimal substrate specificity.

Here, I will present a high-throughput approach we have developed to engineer enhanced variants that rescue the toxicity of proteins implicated in ALS/FTD and PD without conferring off-target effects in mammalian cells. I will also highlight our efforts to characterize human disaggregase proteins that can counter protein misfolding. 

Meredith Jackrel, Ph.D.

Assistant Professor of Chemistry
Washington University of St. Louis