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SUMMARY:Cytoplasm\, nucleus and endoplasmic reticulum differ in their resp
 onses towards toxic protein aggregation - Dr. Mark S. Hipp\, Max Planck In
 stitute of Biochemistry
DTSTART:20160608T093000Z
DTEND:20160608T103000Z
UID:TALK66447@talks.cam.ac.uk
CONTACT:Jerome Charmet
DESCRIPTION:Amyloid-like protein aggregation is associated with neurodegen
 eration and many other pathologies. The nature of the toxic aggregate spec
 ies and their mechanism of action remain elusive. We investigated how the 
 quality control systems of different cellular compartments handle aggregat
 ion-prone proteins\, by utilizing beta-sheet proteins that were designed d
 e novo to form amyloid-like fibrils.\nOf the three compartments tested\, a
 ggregation in the cytoplasm was most toxic\, and cytoplasmic aggregates in
 terfered with nucleo-cytoplasmic protein and RNA transport. In contrast\, 
 the same proteins did not exhibit overt toxicity when forming inclusions i
 n the nucleus. Protein aggregation in the cytoplasm\, but not the nucleus\
 , caused the sequestration and mislocalization of proteins containing diso
 rdered and low complexity sequences\, including multiple factors of the nu
 clear import and export machinery. \nTargeting the beta-proteins to the ER
  also resulted in a strong reduction of toxicity. The aggregation-prone pr
 oteins were retained within the ER in a soluble polymeric state\, despite 
 reaching very high concentrations exceeding those of ER-resident molecular
  chaperones.\nOur findings demonstrate a remarkable capacity of the ER and
  the nucleus to prevent the formation of toxic aggregates. However the two
  compartments use very different strategies to reduce the load of toxic ag
 gregates and prevent harmful interactions.
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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