Human brain nascent polypeptide-associated complex alpha subunit is decreased in patients with Alzheimer' s disease and Down syndrome.
Nascent polypeptide-associated complex (NAC) protein, a heterodimeric complex of alpha- and beta-subunits, prevents mistargeting of nascent polypeptide chains to the endoplasmic reticulum membranes. alpha-NAC has sequence similarities with transcription-regulating proteins and has been reported to function as a transcriptional coactivator potentiating c-Jun-mediated transcription. Performing gene hunting using differential display-polymerase chain reaction, a downregulated sequence in the frontal cortex of patients with Alzheimer's disease (AD) and Down syndrome (DS) with AD-like neuropathology was identified as a-NAC with 100% homology. The significant decrease in alpha-NAC mRNA was shown by semiquantitative reverse transcription-polymerase chain reaction, and in parallel, the significant decrease of alpha-NAC protein, which was even more pronounced when related to either actin or neuron-specific enolase levels, was also observed in both disorders. Linear regression analysis revealed a strong, significant correlation between alpha-NAC protein and mRNA expression. In fetal DS brain, however, mRNA levels of alpha-NAC were comparable between DS and controls, suggesting that the decrease in alpha-NAC might be involved in the pathology of neurodegenerative diseases. The decrease in alpha-NAC as a transcriptional coactivator could contribute to the characteristic decline of the c-Jun-mediated transcriptional machinery and could function as the complementary mechanism in c-Jun-mediated apoptosis. Decreased alpha-NAC may result in the mistargeting, mistranslation, and proteolysis of proteins by affecting overall NAC function.
Kim
Seong Hwan
SH
Department of Pediatrics, University of Vienna, Austria.
Shim
Ki Shuk
KS
Lubec
Gert
G
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D018076:DNA, Complementary / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D018832:Molecular Chaperones; D021122:Protein Subunits; D012333:RNA, Messenger; D015534:Trans-Activators; C096099:nascent-polypeptide-associated complex