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SUMMARY:Protein misfolding: Influence of the cellular environment - Anne B
 ertolotti - LMB - Cambridge
DTSTART:20071128T103000Z
DTEND:20071128T113000Z
UID:TALK9333@talks.cam.ac.uk
CONTACT:Giorgio Favrin
DESCRIPTION:Deposition of proteins of aberrant conformation is the hallmar
 k of several neurodegenerative diseases such as Alzheimer’s disease\, Pa
 rkinson’s disease\, Huntington’s disease (HD)\, amyotrophic lateral sc
 lerosis and prion disorders. Proteins forming inclusions in neurodegenerat
 ive disease are synthetized in different compartments but aggregates are f
 ound in the cytosol\, nucleus or extracellular space\, leading us to quest
 ion whether the subcellular environment could somehow modulate aggregation
  propensity of the disease associated proteins. We found that aggregation 
 of a protein containing a polyQ stretch of pathological length is abolishe
 d when its expression is targeted to the endoplasmic reticulum. Once retro
 gradely transported outside of the endoplasmic reticulum\, the aggregation
 -prone polyQ containing protein recovers its ability to aggregate. When ex
 pressed in the mitochondria\, a protein containing 73 glutamines is entire
 ly soluble while the nucleo-cytosolic equivalent has an extremely high ten
 dency to aggregate. Preventing aggregation of an expanded polyQ protein wh
 ile achieving high levels of expression is an unprecedented finding. Our d
 ata imply that polyQ aggregation is a property restricted to the nucleo-cy
 tosolic compartment and suggest the existence of compartment-specific co-f
 actors promoting or preventing aggregation of pathological proteins. Seeki
 ng for polyQ aggregation modulators\, we found that the proline-rich regio
 n in Huntingtin acts as a profound cis-acting modulator of expanded polyQ 
 aggregation and toxicity in yeast. 
LOCATION:Todd Hamied Room\,  Department of Chemistry
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