Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing.
The amyloid precursor protein (APP) gives rise toc beta-amyloid peptides, which are the main constituents of senile plaques in brains of Alzheimer's disease patients. Non-amyloidogenic processing of the APP can be stimulated by phorbol esters (PEs) and by intracellular diacylglycerol (DAG) generation. This led to the hypothesis that classical and novel protein kinase Cs (PKCs), which are activated by DAG/PEs, regulate APP processing. However, in addition to PKCs, there are other DAG/PE receptors present in neurons that may participate in the modulation of APP processing. Munc13-1, a presynaptic protein with an essential role in synaptic vesicle priming, represents such an alternative target of the DAG second messenger pathway. Using Munc13-1 knock-out mice and knock-in mice expressing a Munc13-1(H567K) variant deficient in DAG/PE binding, we determined the relative contributions of PKCs and Munc13-1 to PE-stimulated secretory APP processing. We establish that, in addition to PKC, Munc13-1 significantly contributes to the regulation of secretory APP metabolism.
Rossner
Steffen
S
Paul Flechsig Institut für Hirnforschung, Abteilung Neurochemie, Universität Leipzig, Jahnallee 59, D-04109 Leipzig, Germany. rossn@medizin.uni-leipzig.de
Fuchsbrunner
Katrin
K
Lange-Dohna
Christine
C
Hartlage-Rübsamen
Maike
M
Bigl
Volker
V
Betz
Andrea
A
Reim
Kerstin
K
Brose
Nils
N
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004075:Diglycerides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D010703:Phorbol Esters / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D004075:Diglycerides; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D010703:Phorbol Esters; C485548:UNC13B protein, human; C485549:Unc13b protein, mouse; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D013755:Tetradecanoylphorbol Acetate