Changes in Cellular Nucleic Acid Binding Protein with Aging and Degenerative Disease

Abstract

Background: The ZNF9 gene on chromosome 3 encodes the Cellular Nucleic Acid Binding Protein (CNBP), a ubiquitously expressed protein that is highly conserved among vertebrates. An expansion in the first intron of CNBP results in Myotonic Dystrophy Type II, and it is a potential modifier of β‐secretase (BACE), the rate‐limiting event in the formation of the Aβ peptide, implicated in Alzheimer's disease.Objective: To determine if there are changes in CNBP with aging or degenerative disease, and begin elucidating the effect on BACE.Methods: AAV2 was used to overexpress CNBP in cell culture and in mouse skeletal muscle. Both were evaluated by ELISA, western blot, and RT‐PCR. CNBP levels were evaluated across the murine lifespan.ResultsThere is a significant increase in CNBP murine muscle and brain with aging. Three‐fold overexpression of CNBP was achieved in vivo, leading to an increase in BACE1 protein (p<0.01) and increase in Aβ (p<0.01). In culture, increased BACE1 was detectable after 24 hours. The steady state amount of BACE1 mRNA did not change in vivo or in vitro after CNBP AAV2 treatment.Conclusions: These data support the hypothesis that CNBP regulates BACE1, and that this effect is largely post‐transcriptional or translational. Future studies will elucidate the effect of CNBP knockdown on BACE1 and Aβ related pathology. Supported by NIH/NINDS R01 NS058382 and NIH/HL T32 086341.