Calnuc binds to Alzheimer's beta-amyloid precursor protein and affects its biogenesis.
Calnuc, a Golgi calcium binding protein, plays a key role in the constitution of calcium storage. Abnormal calcium homeostasis has been linked to Alzheimer's disease (AD). Excessive production and/or accumulation of beta-amyloid (Abeta) peptides that are proteolytically derived from the beta-amyloid precursor protein (APP) have been linked to the pathogenesis of AD. APP has also been indicated to play multiple physiological functions. In this study, we demonstrate that calnuc interacts with APP through direct binding to the carboxyl-terminal region of APP, possibly in a calcium-sensitive manner. Immunofluorescence study revealed that the two proteins co-localize in the Golgi in both cultured cells and mouse brains. Over-expression of calnuc in neuroblastoma cells significantly reduces the level of endogenous APP. Conversely, down-regulation of calnuc by siRNA increases cellular levels of APP. Additionally, we show that over-expression of calnuc down-regulates the APP mRNA level and inhibits APP biosynthesis, which in turn results in a parallel reduction of APP proteolytic metabolites, sAPP, CTFs and Abeta. Furthermore, we found that the level of calnuc was significantly decreased in the brain of AD patients as compared with that of age-matched non-AD controls. Our results suggest a novel function of calnuc in modulating the levels of APP and its proteolytic metabolites, which may further affect the patho/physiological functions of APP including AD pathogenesis.
Lin
Ping
P
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92037, USA.
Li
Feng
F
Zhang
Yun-Wu
YW
Huang
Haining
H
Tong
Gary
G
Farquhar
Marilyn Gist
MG
Xu
Huaxi
H
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D011180:Postmortem Changes; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014162:Transfection; D020798:Two-Hybrid System Techniques
D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D002118:Calcium