Cellular Nucleic Acid Binding Protein (CNBP) in Aging and Disease

Abstract

Type II Myotonic Dystrophy is caused by a tetranucleotide expansion in the ZNF9 gene, which encodes the single strand RNA binding protein CNBP (Cellular Nucleic Acid Binding Protein). CNBP also regulates the activity of â‐secretase (BACE1), the rate limiting enzyme in the production of the amyloid‐â peptide (Aâ), and also instrumental in the development of Alzheimer's disease (AD). The activity and protein levels of BACE1 increase in Alzheimer's disease, in normal aging, and in Inclusion Body Myositis, an age‐related, degenerative disease of the skeletal musculature. In this study, we sought to characterize CNBP in both age and disease state. We examined levels of CNBP protein and BACE1 and protein and activity across the normal life span of the mouse, and in individuals with AD and age matched controls. A fluorometric â‐secretase assay was developed to measure both â‐secretase activity and protein levels. Using this and related techniques, enzymatic activity and protein levels were measured in aging mice, and in human tissue samples. Cell culture studies demonstrated that CNBP regulates BACE1 protein and activity, most likely at the mRNA level. â‐secretase increases in the disease state, and CNBP also increased slightly with age. These data suggest CNBP may regulate â‐secretase in vivo and in vitro, and may contribute to the development of AD and other age‐related degenerative diseases. Supported by NIH NS058382.