G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation.
Early-onset familial Alzheimer's disease (AD) is most commonly associated with the mutations in presenilin-1 (PS1). PS1 is the catalytic component of the γ-secretase complex, which cleaves amyloid precursor protein to produce amyloid-β (Aβ), the major cause of AD. Presenilin enhancer 2 (Pen2) is critical for activating γ-secretase and exporting PS1 from endoplasmic reticulum (ER). Among all the familial AD-linked PS1 mutations, mutations at the G206 amino acid are the most adjacent position to the Pen2 binding site. Here, we characterized the effect of a familial AD-linked PS1 G206D mutation on the PS1-Pen2 interaction and the accompanied alteration in γ-secretase-dependent and -independent functions. We found that the G206D mutation reduced PS1-Pen2 interaction, but did not abolish γ-secretase formation and PS1 endoproteolysis. For γ-secretase-dependent function, the G206D mutation increased Aβ42 production but not Notch cleavage. For γ-secretase-independent function, this mutation disrupted the ER calcium homeostasis but not lysosomal calcium homeostasis and autophagosome maturation. Impaired ER calcium homeostasis may due to the reduced mutant PS1 level in the ER. Although this mutation did not alter the cell survival under stress, both increased Aβ42 ratio and disturbed ER calcium regulation could be the mechanisms underlying the pathogenesis of the familial AD-linked PS1 G206D mutation.
Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan.
Wei-Ting
WT
Chen
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Yi-Fang
YF
Hsieh
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
Yan-Jing
YJ
Huang
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Che-Ching
CC
Lin
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Yen-Tung
YT
Lin
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Yu-Chao
YC
Liu
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
Cheng-Chang
CC
Lien
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. hjcheng@ym.edu.tw.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan. hjcheng@ym.edu.tw.|Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan. hjcheng@ym.edu.tw.|Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan. hjcheng@ym.edu.tw.|Institute of Brain Science, School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong Street, Taipei, 112, Taiwan. hjcheng@ym.edu.tw.
Irene Han-Juo
IH
Cheng
D000544:Alzheimer Disease / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; C555827:presenilin enhancer 2, mouse; D002118:Calcium
Alzheimer’s disease; Amyloid beta; Calcium; G206D mutation; Presenilin enhancer 2; Presenilin-1