Affiliations: 1) Department of Biology, University of Dayton, Dayton, OH; 2) Institution of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan; 3) National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan; 4) Premedical Program, University of Dayton, Dayton, OH; 5) Center for Tissue Regeneration & Engineering (TREND), University of Dayton, Dayton, OH; 6) Integrative Science and Engineering (ISE), University of Dayton, Dayton, OH; 7) Center for Genomic Advocacy (TCGA), Indiana State University, Terre Haute, IN
Keywords: w. genetic modifiers of disease; a. caspases
Alzheimer’s disease (AD), an age-related progressive neurodegenerative disorder, exhibits reduced cognitive functions with no cure to date. One of the reasons for AD is the extracellular accumulation of Amyloid-beta 42 (Aβ42) plaques. We misexpressed human Aβ42 in the developing retina of Drosophila, which exhibits AD-like neuropathology. Accumulation of Aβ42 plaque(s) triggers aberrant signaling resulting in neuronal cell death by unknown mechanism(s). We screened for microRNAs (miRNAs) which post-transcriptionally regulate expression of genes by degrading mRNA of the target genes. In a forward genetic screen with candidate miRNAs, we identified miR-277 as a genetic modifier of Aβ42-mediated neurodegeneration. Gain-of-function of miR-277 rescues Aβ42-mediated neurodegeneration whereas loss-of-function of miR-277 enhances Aβ42-mediated neurodegeneration. Moreover, misexpression of higher levels of miR-277 in the GMR>Aβ42 background restores the retinal axonal targeting indicating functional rescue. Furthermore, we have identified head involution defective (hid) as one of the targets of miR-277 by Fly TargetScan and validated by luciferase assay and qPCR. The hid transcript levels are decreased by ̴ 2.3-fold when miR-277 is misexpressed in the GMR>Aβ42 background in comparison to the GMR>Aβ42 fly model. Hence, here we provide a mechanism of how miR-277 modulates Aβ42-mediated neurodegeneration by regulating hid transcript levels and demonstrate its neuroprotective role in Aβ42-mediated neuropathology.