The intersection of neurodegenerative disease and ribosome biogenesis through Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; Fe65) Lisa M. Ogawa McLean1 and Susan J. Baserga1,2,3, 1Departments of Molecular Biophysics and Biochemistry, 2Genetics, and 3Therapeutic Radiology, Yale University and Yale School of Medicine, New Haven, CT
Ribosome biogenesis begins in the nucleolus and is critical for cellular growth and proliferation. Defects in ribosome production are associated with a wide range of pathologies including a number of cancers, as well as a novel group of congenital disorders known as the ribosomopathies. We recently published a genome-wide siRNA screen in the MCF10A human breast epithelial cell line to uncover novel factors required for human ribosome biogenesis (Farley-Barnes et al. 2018). In this screen we identified 139 proteins that upon depletion cause a decrease in the average number of nucleoli per nucleus. One of these hits is the adaptor protein Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; Fe65), associated with the amyloid precursor protein (APP) that is implicated in Alzheimer's disease. In a panel of secondary assays, we revealed a role for APBB1 in both the transcription and processing of the pre-ribosomal RNA (pre-rRNA). Furthermore, RNA polymerase II (RNAPII) chromatin immunoprecipitation (ChIP) in APBB1-depleted SH-SY5Y cells revealed 137 regions with differential RNAPII occupancy (2-fold cutoff). Within these regions are 236 annotated genes, 17% of which yield proteins that localize to the nucleolus. A link between ribosome biogenesis and neurodegeneration is not without precedence; however, specific mechanisms by which ribosome production and neurodegeneration are interconnected has yet to be determined. These results are thus significant as they not only broaden our understanding of the complex regulation of ribosome biogenesis, but they also lend insight into the intersection between ribosome biogenesis and Alzheimer's disease that may lead to a better understanding of neurodegenerative disease and novel avenues for drug discovery.
References Farley-Barnes KI, McCann KL, Ogawa LM, Merkel J, Surovtseva YV, and Baserga SJ. Diverse regulators of human ribosome biogenesis discovered by changes in nucleolar number. Cell Reports 2018, 22(7):1923-1934.
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