Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates.
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.
Cecchi
Cristina
C
Department of Biochemical Sciences.
Baglioni
Serena
S
Fiorillo
Claudia
C
Pensalfini
Anna
A
Liguri
Gianfranco
G
Nosi
Daniele
D
Rigacci
Stefania
S
Bucciantini
Monica
M
Stefani
Massimo
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000494:pharmacology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects*; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D013045:Species Specificity; D013997:Time Factors
D001426:Bacterial Proteins; C108878:HypF protein, Bacteria; D046911:Macromolecular Substances; D002784:Cholesterol; D002118:Calcium