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First published online August 3, 2005
doi: 10.1242/10.1242/jcs.02473
Research Article |
1 Department of Biochemical Sciences
2 Department of Anatomy, Histology and Forensic Medicine
3 Center of Excellence for Molecular and Clinical Studies in Chronic, Inflammatory, Degenerative and Tumoural Diseases for the Development of New Therapies
4 Interuniversity Centre for the Study of the Molecular Basis of Neurodegenerative Diseases, University of Florence, Florence, 50134, Italy
* Author for correspondence (e-mail: stefani{at}scibio.unifi.it)
Accepted 19 April 2005
It has been reported that different tissue or cultured cell types are variously affected by the exposure to toxic protein aggregates, however a substantial lack of information exists about the biochemical basis of cell resistance or susceptibility to the aggregates. We investigated the extent of the cytotoxic effects elicited by supplementing the media of a panel of cultured cell lines with aggregates of HypF-N, a prokaryotic domain not associated with any amyloid disease. The cell types exposed to early, pre-fibrillar aggregates (not mature fibrils) displayed variable susceptibility to damage and to apoptotic death with a significant inverse relation to membrane content in cholesterol. Susceptibility to damage by the aggregates was also found to be significantly related to the ability of cells to counteract early modifications of the intracellular free Ca2+ and redox status. Accordingly, cell resistance appeared related to the efficiency of the biochemical equipment leading any cell line to sustain the activity of Ca2+ pumps while maintaining under control the oxidative stress associated with the increased metabolic rate. Our data depict membrane destabilization and the subsequent early derangement of ion balance and intracellular redox status as key events in targeting exposed cells to apoptotic death.
Key words: Amyloid toxicity, Pre-fibrillar protein aggregates, Conformational diseases, Folding and disease, Protein misfolding and citotoxicity
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