Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Hashimoto, Y. et al.

Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target.

While it has been reported that familial Alzheimer's disease (FAD)-linked mutants of amyloid precursor protein ( APP) and presenilin (PS)2 induce neuronal cytotoxicity in a manner sensitive to antioxidant and pertussis toxin (PTX), little of the mechanism for PS1-mediated neuronal cell death has been characterized. We previously found that multiple mechanisms, different in detail, underlie cytotoxicities by two FAD- linked mutants of APP, using neuronal cells with an ecdysone-controlled expression system. Here we report that this system revealed that (i) low expression of FAD- linked M146L- PS1 caused neuronal cell death, whereas that of wild-type (wt)PS1 did not; (ii) mutation-specific cytotoxicity by M146L- PS1 was sensitive to antioxidant glutathione-ethyl-ester and resistant to Ac-DEVD-CHO; (iii) cytotoxicity by higher expression of wtPS1 was resistant to both; and (iv) cytotoxicity by M146L- PS1 was inhibited by PTX. It was also highly likely that the involved superoxide-generating enzyme was nitric oxide synthase (NOS), and that the PTX-sensitive cytotoxic signal by M146L- PS1 was mediated by none of the G(i/o) proteins. We conclude that M146L- PS1 activates a NOS-mediated cytotoxic pathway via a novel PTX target.[1]

References

Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M146L presenilin 1: involvement of NO synthase via a novel pertussis toxin target. Hashimoto, Y., Ito, Y., Arakawa, E., Kita, Y., Terashita, K., Niikura, T., Nishimoto, I. J. Neurochem. (2002) [Pubmed]

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