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Content archived on 2024-05-14

Molecular mechanisms leading to cystatin c aggregation and amyloidosis in brain haemorrhage patients

Objective



A point mutation in the gene for the human cysteine proteinase inhibitor, cystatin C, causes dementia and brain haemorrhage in patients with Hereditary Cystatin C Amyloid Angiopathy (HCCAA). The protein variant expressed as a result of the mutation, L68Q-cystatin C, is deposited as amyloid in the brain arteries of such patients. The current project aims at the characterization of L68Q-cystatin C, in order to elucidate the molecular mechanisms leading to cystatin C aggregation and amyloidosis and with the perspective to find means of inhibiting the aggregation and thereby prevent amyloid formation. To obtain L68Q-cystatin C in amounts allowing detailed study, expression systems will be developed for recombinant production in Saccharomyces or Aspergillus. Methods will be developed to allow in vitro measurements of the rate of formation of L68Q-cystatin C dimers and higher-order aggregates to define the path leading to amyloid formation. The structure of dimeric L68Q-cystatin C will be studied by NMR spectroscopy or X-ray crystallography, with the aim to develope low-molecular-weight inhibitors to the dimerization process, to be tested for potential as therapeutic agents by the in vitro methods developed.

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RGI - Research grants (individual fellowships)

Coordinator

LUND UNIVERSITY
EU contribution
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Address
Wallenberg laboratoriet, University Hospital
221 85 LUND
Sweden

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Total cost

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Participants (1)

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