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SUMMARY:Misfolding of proteins with polyglutamine expansion is facilitated
  by proteosomal chaperones - Dr. Anne Bertolotti\, MRC Laboratory of Molec
 ular Biology\, Cambridge
DTSTART:20090929T144500Z
DTEND:20090929T151500Z
UID:TALK18692@talks.cam.ac.uk
CONTACT:Hannah Critchlow
DESCRIPTION:This talk is part of the Cambridge Clinical Neuroscience and M
 ental Health Symposium\, 29th - 30th September 2009 at West Road Concert H
 all. This event is free to attend for cambridge neuroscientists although r
 egistration is required. To register\, and for further information\, pleas
 e visit: http://www.neuroscience.cam.ac.uk/cnmhs/\n\nAbstract: Deposition 
 of proteins of aberrant conformation is the hallmark of several neurodegen
 erative diseases such as Alzheimer’s disease\, Parkinson’s disease\, H
 untington’s disease (HD)\, amyotrophic lateral sclerosis and prion disor
 ders. Proteins forming inclusions in neurodegenerative disease are synthet
 ized in different compartments but aggregates are found in the cytosol\, n
 ucleus or extracellular space\, leading us to question whether the subcell
 ular environment could somehow modulate aggregation propensity of the dise
 ase associated proteins. We found that aggregation of a protein containing
  a polyQ stretch of pathological length is abolished when its expression i
 s targeted to the endoplasmic reticulum. Once retrogradely transported out
 side of the endoplasmic reticulum\, the aggregation-prone polyQ containing
  protein recovers its ability to aggregate. When expressed in the mitochon
 dria\, a protein containing 73 glutamines is entirely soluble while the nu
 cleo-cytosolic equivalent has an extremely high tendency to aggregate. Our
  data imply that polyQ aggregation is a property restricted to the nucleo-
 cytosolic compartment and suggest the existence of compartment-specific co
 -factors promoting or preventing aggregation of pathological proteins. \nW
 hile it is clear that the polyQ expansion causes aggregation and provokes 
 neurodegeneration\, other factors than the polyQ expansion modulate aggreg
 ation propensity and disease onset. In addition to the influence of the ce
 llular environment on mutant Huntingtin aggregation\, we found that the pr
 oline-rich region in Huntingtin\, immediately adjacent to the polyQ expans
 ion\, profoundly antagonizes aggregation and toxicity of mutant Huntingtin
 . Thus\, some trigger ought to be required to alleviate the inhibitory fun
 ction of the proline-rich region and initiate aggregation of mutant Huntin
 gtin. We found that this conversion form soluble to misfolded Huntingtin i
 s facilitated by proteasomal ATPases. We propose that aggregation of prote
 ins with expanded polyglutamine is not a consequence of a proteolytic fail
 ure of the 20S proteasome. Rather\, aggregation is elicited when the unfol
 dase subunits of the 19S particle function independently of proteolysis.\n
 \nReferences:\n1.	Rousseau E\, Dehay B\, Ben-Haiem L\, Trottier Y\, Morang
 e M\, Bertolotti A (2004) Targeting expression of expanded polyglutamine p
 roteins to the endoplasmic reticulum or mitochondria prevents their aggreg
 ation. Proc Natl Acad Sci U S A 101:9648–9653.\n2.	Dehay B\, Bertolotti 
 A (2006) Critical role of the proline-rich region in Huntingtin for aggreg
 ation and cytotoxicity in yeast. J Biol Chem 281:35608–35615.\n3.	Dehay 
 B\, Weber C\, Trottier Y\, Bertolotti A (2007) Mapping of the epitope of m
 onoclonal antibody 2B4 to the proline-rich region of human Huntingtin\, a 
 region critical for aggregation and toxicity. Biotechnol J 2:559–564.\n4
 .	Bertolotti A (2008) Protein misfolding in neurodegenerative diseases. De
 mentia forum 5:17–20.\n5.	Rousseau E\, Kojima R\, Hoffner G\, Djian P\, 
 Bertolotti A (2009) Misfolding of proteins with a polyglutamine expansion 
 is facilitated by proteasomal chaperones. J Biol Chem 284:1917–1929.\n\n
LOCATION:West Road Concert Hall
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