LMB Seminar: Pharmacological Adaptation of Proteostasis to Ameliorate Aging-associated Degenerative Diseases

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• Jeffery W. Kelly, The Scripps Research Institute
• Tuesday 07 November 2023, 11:00-12:00
• In person in the Max Perutz Lecture Theatre (CB2 0QH) and via Zoom, link: https://mrc-lmb-cam-ac-uk.zoom.us/j/94698100541?pwd=L0RIZUcvY0dvYjhaRW5VU0pXNThKUT09.

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The cellular protein homeostasis, or proteostasis, network regulates proteome function by controlling ribosomal protein synthesis, chaperone- and chaperonin-mediated protein folding, protein trafficking, proteasome and lysosomal protein degradation, and related processes. Stress-responsive signaling pathways match proteostasis network capacity with demand in each subcellular compartment to maintain or alter cellular homeostasis. The beginning of the seminar will focus on how a protein homeostatic deficiency leading to organ system degeneration in a spectrum of aging-associated amyloid diseases can be stopped or slowed utilizing small molecule kinetic stabilizers–a pharmacological approach to ameliorating neurodegeneration. The clinical efficacy of tafamidis, a transthyretin kinetic stabilizer approved for use in >50 countries for the amelioration of polyneuropathy and cardiomyopathy, will be covered in the context of what we have learned about amyloid diseases and what remains to be learned. The data strongly support the hypothesis that protein aggregation is the driver of neurodegeneration through a mechanism(s) being sought. The second half of the talk will focus on how we discovered drug candidates via high-throughput screens that adapt proteostasis by enhancing lysosomal flux. One of these compounds extends lifespan and healthspan in C. elegans (a collaboration with the Malene Hansen lab), and ameliorates Parkinson’s pathology in a neuronal model, studies carried out in collaboration with the Laushel lab. Another mTOR inhibitor-independent autophagy activator hit reduces cytotoxic axonal mutant prion protein aggregate levels within endosomes of murine primary hippocampal neurons and normalizes axonal trafficking deficiencies, studies performed in collaboration with the Encalada Lab. In addition, a subset of hits from the HTS robustly clear phosphorylated and insoluble tau, while reducing tau-mediated neuronal stress vulnerability in an iPSC-derived neuronal familial tauopathy model, studies carried out in collaboration with the Haggarty Lab. We will show data supporting the hypothesis that mTOR inhibition-independent autophagy activators will be useful for ameliorating neurodegenerative diseases.

This talk is part of the MRC LMB Seminar Series series.

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• In person in the Max Perutz Lecture Theatre (CB2 0QH) and via Zoom, link: https://mrc-lmb-cam-ac-uk.zoom.us/j/94698100541?pwd=L0RIZUcvY0dvYjhaRW5VU0pXNThKUT09
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