miR-277 targets hid to ameliorate Aβ42-mediated neurodegeneration in Drosophila eye model of Alzheimer’s Disease
Anuradha Venkatakrishnan, Prajakta D. Deshpande
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.
Madhuri Kango-Singh, Amit Singh
Primary Advisor's Department
Stander Symposium project, College of Arts and Sciences
United Nations Sustainable Development Goals
Good Health and Well-Being
"miR-277 targets hid to ameliorate Aβ42-mediated neurodegeneration in Drosophila eye model of Alzheimer’s Disease" (2022). Stander Symposium Projects. 2431.