Leveraging Pathobiology of Self-Perpetuating Amyloid Strains for Translational Protein Misfolding Targeted Therapeutics
Tuesday, October 17 - 10:30 – 12:30
For most of the past 70 years of molecular biology, amino acid sequences encoded in genomic DNA and environmental context have been the primary consideration for functional protein folding. However, many proteins acquire alternative conformations and proceed through two-step nucleation to achieve paracrystalline variants that can faithfully reproduce, for example in case of self-perpetuating cross-β fibrils (amyloids). These amyloids are associated with more than 40 devastating diseases, including Alzheimer’s disease and various systemic and localized amyloidoses. Recent evidence suggests that amyloids can exist as structural and functional variants called strains, but surprisingly little is known about the steps at which strain formation is controlled, the molecular mechanisms underlying strain patterns, or the role of polymorphic strains in pathogenicity. Our goal in the workshop will be to inform therapeutic strategies for amyloidoses by illuminating the dynamic nature
of structurally and functionally variant protein aggregates and defining the cellular and biophysical parameters that underlie their function with different models including yeast, animal models, and human organoids.
Topics to be covered:
• How do amyloid strains form and spread?
• Are there common structural dynamics to proteopathic amyloid strains?
• Are there cell type-specific impacts of amyloidogenic strains on brain functions?
• How is structure linked to Ab and tau phenotypes, pathologies, and cross-seeding capabilities?
• How can yeast, animal models, and human organoids report on pathobiology
• How to translate pathobiology of amyloid strains for therapeutics?
Opportunities for Pharmacological Manipulation of the Ubiquitin Proteasome System from PROTACS to Proteasome Enhancement
Tuesday, October 27 - 13:30 – 16:00
Enabled by the exciting clinical progression of PROTACbased therapies, our understanding of the pharmacological opportunity held by the ubiquitin proteasome system has taken a giant leap in recent years. Still, our limited knowledge of fundamental biology and chemistry is hindering the ongoing efforts to translate robust candidates into the clinic. In this workshop, we will cover the vital technical scientific challenges that need to be addressed to accelerate successful PROTAC therapies through the clinic in the future. Also, we will discuss the opportunities and findings on targeting protein degradation using the latest PROTAC approaches.
Topics to be covered:
• How can the ubiquitin system be cooped for targeted protein degradation?
• How can protein targeting chimeric molecule (PROTACS) be used to target specific proteins for degradation?
• Can proteasome capacity be upregulated?
• Can ubiquitin dependant protein degradation be enhanced?
• How can degradation of intrinsically disordered proteins (IDPs) be stimulated?