Nascent polypeptide-associated complex (NAC) protein, a heterodimeric complex of α- and β-subunits, prevents mistargeting of nascent polypeptide chains to the endoplasmic reticulum membranes. α-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 downregu-lated sequence in the frontal cortex of patients with Alzheimer's disease (AD) and Down syndrome (DS) with AD-like neuropathology was identified as α-NAC with 100% homology. The significant decrease in α-NAC mRNA was shown by semiquantitative reverse transcription-polymerase chain reaction, and in parallel, the significant decrease of α-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 α-NAC protein and mRNA expression. In fetal DS brain, however, mRNA levels of α-NAC were comparable between DS and controls, suggesting that the decrease in α-NAC might be involved in the pathology of neurodegenerative diseases. The decrease in α-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 α-NAC may result in the mistargeting, mistranslation, and proteolysis of proteins by affecting overall NAC function.
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