University of Cambridge > Talks.cam > Clinical Neuroscience and Mental Health Symposium > Misfolding of proteins with polyglutamine expansion is facilitated by proteosomal chaperones

Misfolding of proteins with polyglutamine expansion is facilitated by proteosomal chaperones

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  • UserDr. Anne Bertolotti, MRC Laboratory of Molecular Biology, Cambridge
  • ClockTuesday 29 September 2009, 15:45-16:15
  • HouseWest Road Concert Hall.

If you have a question about this talk, please contact Hannah Critchlow.

This talk is part of the Cambridge Clinical Neuroscience and Mental Health Symposium, 29th – 30th September 2009 at West Road Concert Hall. This event is free to attend for cambridge neuroscientists although registration is required. To register, and for further information, please visit: http://www.neuroscience.cam.ac.uk/cnmhs/

Abstract: Deposition of proteins of aberrant conformation is the hallmark of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (HD), amyotrophic lateral sclerosis and prion disorders. Proteins forming inclusions in neurodegenerative disease are synthetized in different compartments but aggregates are found in the cytosol, nucleus or extracellular space, leading us to question 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 abolished when its expression is targeted to the endoplasmic reticulum. Once retrogradely transported outside of the endoplasmic reticulum, the aggregation-prone polyQ containing protein recovers its ability to aggregate. When expressed in the mitochondria, a protein containing 73 glutamines is entirely soluble while the nucleo-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. While it is clear that the polyQ expansion causes aggregation and provokes neurodegeneration, other factors than the polyQ expansion modulate aggregation propensity and disease onset. In addition to the influence of the cellular environment on mutant Huntingtin aggregation, we found that the proline-rich region in Huntingtin, immediately adjacent to the polyQ expansion, profoundly antagonizes aggregation and toxicity of mutant Huntingtin. Thus, some trigger ought to be required to alleviate the inhibitory function of the proline-rich region and initiate aggregation of mutant Huntingtin. We found that this conversion form soluble to misfolded Huntingtin is facilitated by proteasomal ATPases. We propose that aggregation of proteins with expanded polyglutamine is not a consequence of a proteolytic failure of the 20S proteasome. Rather, aggregation is elicited when the unfoldase subunits of the 19S particle function independently of proteolysis.

References: 1. Rousseau E, Dehay B, Ben-Haiem L, Trottier Y, Morange M, Bertolotti A (2004) Targeting expression of expanded polyglutamine proteins to the endoplasmic reticulum or mitochondria prevents their aggregation. Proc Natl Acad Sci U S A 101 :9648–9653. 2. Dehay B, Bertolotti A (2006) Critical role of the proline-rich region in Huntingtin for aggregation and cytotoxicity in yeast. J Biol Chem 281:35608–35615. 3. Dehay B, Weber C, Trottier Y, Bertolotti A (2007) Mapping of the epitope of monoclonal antibody 2B4 to the proline-rich region of human Huntingtin, a region critical for aggregation and toxicity. Biotechnol J 2 :559–564. 4. Bertolotti A (2008) Protein misfolding in neurodegenerative diseases. Dementia forum 5:17–20. 5. 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.

This talk is part of the Clinical Neuroscience and Mental Health Symposium series.

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