Presenilin-1 protects against neuronal apoptosis caused by its interacting protein PAG.
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.
Zhou
Yan
Y
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Zhang
Wanjiang
W
Easton
Rachael
R
Ray
James W
JW
Lampe
Patricia
P
Jiang
Zhihong
Z
Brunkan
Anne L
AL
Goate
Alison
A
Johnson
Eugene M
EM
Wu
Jane Y
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005091:Exons; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D010544:Peroxidases / Q000378:metabolism; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D010957:Plasmids / Q000494:pharmacology; D053764:Presenilin-1; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology
D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; C508853:PSEN1 protein, human; D053764:Presenilin-1; D010544:Peroxidases; C489898:Prdx1 protein, rat; C515940:PRDX1 protein, human; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins