The regulation of presenilin-1 by nerve growth factor.
Presenilin-1 (PS1) protein concentration is linked to neuronal development and to the pathogenesis of Alzheimer's disease, yet little is known about the biological factors and mechanisms that control cellular levels of PS1 protein. As PS1 levels are highest in the developing brain, we tested whether neurotrophin-induced differentiation influences PS1 expression using neuronotypic pheochromocytoma (PC12) cells. Treatment of PC12 cells with nerve growth factor (NGF) caused approximately 60-75% increases in the steady-state levels of endogenous PS1 N- and C-terminal fragments. PS1 protein accumulation was dose-responsive to NGF and required the presence of the TrkA NGF receptor tyrosine kinase. NGF also induced PS1 fragment accumulation in cultured explants of rat dorsal root ganglia. Quantitative northern blot analysis using PC12 cultures indicated that NGF did not increase steady-state PS1 mRNA levels. However, pulse-chase experiments indicated that NGF slowed the degradation rate of endogenous PS1 fragments, increasing the half-life from t(1/2) @22.5 to @25.0 h. This increase in half-life was insufficient to account for the approximately 60-75% increase in PS1 fragment levels measured in NGF-treated cells. Thus, NGF may regulate PS1 protein concentration in NGF-responsive cells by a complex mechanism that increases PS1 fragment production independent of holoprotein synthesis.
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Department of Neurology, Emory University School of Medicine, Woodruff Memorial Building, Atlanta, Georgia, USA.
Lah
J J
JJ
Levey
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AI
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006706:Homeostasis; D008565:Membrane Proteins; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015854:Up-Regulation
D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D020917:Receptor, trkA