Abstract
Mutations in the presenilin-1 (PS-1) gene account for a significant fraction of familial Alzheimer's disease. The biological function of PS-1 is not well understood. We report here that the proliferation-associated gene (PAG) product a protein of the thioredoxin peroxidase family interacts with PS-1. Microinjection of a plasmid expressing PAG into superior cervical ganglion (SCG) sympathetic neurons in primary cultures led to apoptosis. Microinjection of plasmids expressing wild-type PS-1 or a PS-1 mutant with a deletion of exon 10 (PS1dE10) by themselves had no effect on the survival of primary SCG neurons. However co-injection of wild-type PS-1 with PAG prevented neuronal death whereas co-injection with the mutant PS-1 did not affect PAG-induced apoptosis. Furthermore overexpression of PAG accelerated SCG neuronal death induced by nerve growth factor deprivation. This sensitizing effect was also blocked by wild-type PS-1 but not by PS1dE10. These results establish an assay for studying the function of PS-1 in primary neurons reveal the neurotoxicity of a thioredoxin peroxidase demonstrate a neuroprotective activity of the wild-type PS-1 and suggest possible involvement of defective neuroprotection by PS-1 mutants in neurodegeneration.
Original language | English (US) |
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Pages (from-to) | 126-138 |
Number of pages | 13 |
Journal | Neurobiology of Disease |
Volume | 9 |
Issue number | 2 |
DOIs | |
State | Published - Mar 2002 |
Funding
We thank Drs. J. Gitlin and P. Seubert for generously providing anti-PS-1 antibodies, Maribel Martinez for excellent technical assistance, and members of the Wu laboratory for critically reading the manuscript. This work is supported by grants from the NIH, the Alzheimer’s Association, the American Health Assistance Foundation, the Washington University Alzheimer’s Disease Research Center, and the Leukemia Society of America Scholarship to J.Y.W. and the NIH to A.G., E.M.G., and J.Y.W.
ASJC Scopus subject areas
- Neurology