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SUMMARY:LMB Seminar: Pharmacological Adaptation of Proteostasis to Amelior
 ate Aging-associated Degenerative Diseases - Jeffery W. Kelly\, The Scripp
 s Research Institute
DTSTART:20231107T110000Z
DTEND:20231107T120000Z
UID:TALK194860@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:The cellular protein homeostasis\, or proteostasis\, network r
 egulates proteome function by controlling ribosomal protein synthesis\, ch
 aperone- and chaperonin-mediated protein folding\, protein trafficking\, p
 roteasome and lysosomal protein degradation\, and related processes. Stres
 s-responsive signaling pathways match proteostasis network capacity with d
 emand in each subcellular compartment to maintain or alter cellular homeos
 tasis. The beginning of the seminar will focus on how a protein homeostati
 c deficiency leading to organ system degeneration in a spectrum of aging-a
 ssociated amyloid diseases can be stopped or slowed utilizing small molecu
 le kinetic stabilizers–a pharmacological approach to ameliorating neurod
 egeneration. The clinical efficacy of tafamidis\, a transthyretin kinetic 
 stabilizer approved for use in >50 countries for the amelioration of polyn
 europathy and cardiomyopathy\, will be covered in the context of what we h
 ave learned about amyloid diseases and what remains to be learned. The dat
 a strongly support the hypothesis that protein aggregation is the driver o
 f neurodegeneration through a mechanism(s) being sought. The second half o
 f the talk will focus on how we discovered drug candidates via high-throug
 hput screens that adapt proteostasis by enhancing lysosomal flux. One of t
 hese compounds extends lifespan and healthspan in C. elegans (a collaborat
 ion with the Malene Hansen lab)\, and ameliorates Parkinson’s pathology 
 in a neuronal model\, studies carried out in collaboration with the Laushe
 l 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 defi
 ciencies\, studies performed in collaboration with the Encalada Lab. In ad
 dition\, a subset of hits from the HTS robustly clear phosphorylated and i
 nsoluble tau\, while reducing tau-mediated neuronal stress vulnerability i
 n an iPSC-derived neuronal familial tauopathy model\, studies carried out 
 in collaboration with the Haggarty Lab. We will show data supporting the h
 ypothesis that mTOR inhibition-independent autophagy activators will be us
 eful for ameliorating neurodegenerative diseases.
LOCATION:In person in the Max Perutz Lecture Theatre (CB2 0QH) and via Zoo
 m\, link: https://mrc-lmb-cam-ac-uk.zoom.us/j/94698100541?pwd=L0RIZUcvY0dv
 YjhaRW5VU0pXNThKUT09
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