BEGIN:VCALENDAR
VERSION:2.0
PRODID:-//Talks.cam//talks.cam.ac.uk//
X-WR-CALNAME:Talks.cam
BEGIN:VEVENT
SUMMARY:Therapeutic manipulations of phosphatases and kinases controlling 
 protein quality control systems: From the bench\, to the clinic and back -
  Anne Bertolotti
DTSTART:20240209T150000Z
DTEND:20240209T160000Z
UID:TALK211123@talks.cam.ac.uk
CONTACT:90994
DESCRIPTION:The deposition of misfolded proteins is a defining feature of 
 many age-dependent human diseases\, including the increasingly prevalent n
 eurodegenerative diseases. Why aggregation-prone proteins accumulate in ag
 ed cells remains largely unclear. Cells normally strive to ensure that pro
 teins get correctly folded and have powerful and sophisticated mechanisms 
 to maintain protein homeostasis (proteostasis) under adverse conditions. H
 owever\, with age and in diseases\, the cellular defence systems against m
 isfolded proteins are overwhelmed\, leading to the accumulation of misfold
 ed proteins with devastating consequences for cells and organism. \nIn pri
 nciple\, improving the cells’ ability to deal with misfolded proteins co
 uld represent a generic approach to reduce the pathology in diverse protei
 n misfolding diseases. My lab has identified powerful small drug-like mole
 cules that safely boost a natural defence system against misfolded. \nThes
 e small molecules inhibit serine/threonine phosphatases controlling the te
 rmination of a proteostatic pathway\, an interesting finding because phosp
 hatases were previously thought to be undruggable. The inhibitors have dem
 onstrated therapeutic effects in various models of neurodegenerative disea
 ses. This work demonstrates that generic approaches aimed at helping cells
  to survive protein quality control failures can be useful to prevent prot
 ein misfolding diseases\, including the devastating neurodegenerative dise
 ases. One of these inhibitors\, Sephin1\, has passed through favourable Ph
 ase 1 clinical trials in 2019 and is being now developed for Charcot-Marie
 -Tooth disease and amyotrophic lateral sclerosis. In 2011\, Guanabenz was 
 found beneficial in a phase 2 clinical trial in ALS\, 10 years after we re
 ported its proteostasis-boosting activity.\n\nThe work on these inhibitors
  has perked our interest in serine/threonine phosphatases\, a class of ver
 y important yet poorly characterized enzymes. In a recent tour de force\, 
 we have deployed a combination of approaches to elucidate the mechanism by
  which an eIF2 phosphatase recruits its large substrate. \n\nExpanding our
  toolbox\, we recently made the unexpected discovery that broadly used ATP
 -competitive inhibitors of eIF2 kinases can paradoxically increase eIF2 ph
 osphorylation by directly binding to and activating a sister kinase result
 ing in functional activation of the pathway rather than the intended inhib
 ition. These findings have broad relevance to kinases. \n
LOCATION:Jean Thomas Lecture theatre\, Sanger Building\, Tennis Court Road
END:VEVENT
END:VCALENDAR