Protein misfolding: Influence of the cellular environment

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• Anne Bertolotti - LMB - Cambridge
• Wednesday 28 November 2007, 10:30-11:30
• Todd Hamied Room, Department of Chemistry.

If you have a question about this talk, please contact Giorgio Favrin.

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. Preventing aggregation of an expanded polyQ protein while achieving high levels of expression is an unprecedented finding. 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. Seeking for polyQ aggregation modulators, we found that the proline-rich region in Huntingtin acts as a profound cis-acting modulator of expanded polyQ aggregation and toxicity in yeast.

This talk is part of the Biophysics Colloquia - (Chemistry) series.

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