Drosophila Eye Model to Investigate How Mutations in OPA1 and Drp-1 Genes Contribute to Neurodegeneration in Alzheimer’s Disease
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder with no known cure to-date. This disease is caused by the extra-cellular accumulation of amyloid-beta 42 (Aβ42) peptides, which ultimately leads to results in neuronal cell death. In our study, we have used Drosophila melanogaster (a.k.a fruit fly) as our model organism (as its genome is highly conserved with humans and any insights generated here can be extrapolated to humans), and have developed transgenic fly model of AD where human Aβ42 peptides can be misexpresssed specifically in differentiating photoreceptor neurons using GAL4/UAS system, without affecting the reproductive ability and life span of flies. One of the hallmarks of AD is generation of Reactive Oxygen Species (ROS) which triggers neuronal cell death. We have found that (1) there is a strong correlation between increased ROS levels and mitochondrial fragmentation and increased levels of ROS and that (2) a fine balance between both mitochondrial fusion, fission events is essential for normal mitochondrial/cellular functions. Any perturbations, in these process results in increased ROS levels which triggers neuronal death. In our study, we have found two dynamin related GTPases (1) opa1 and (2) drp1, which can regulate mitochondrial fusion and fission events respectively. Mutations in opa1 (an early stop signal), produces small unstable mitochondrial proteins, and increases ROS levels in neurons. Thus, we hypothesize that opa1 and drp1 are involved in regulating Aβ42 mediated neurodegeneration. To test our hypothesis, we misexpressed opa1 and drp1 in Aβ42 background (using GAL4/UAS system) and checked for resultant phenotypes in the eye. Our results showed that (1) up-regulating and downregulating opa1 rescues Aβ42 mediated neurodegeneration only in female flies and in male flies eyes respectively, (2) down-regulating drp1 rescues Aβ42 mediated neurodegeneration only in female flies, while (3) up-regulating drp1 did not result in any eye rescues phenotypes. This study has significant bearings on mitochondria’s role in neurodegeneration. Keywords: Alzheimer’s Disease, Neurodegeneration, Reactive Oxygen Species, Mitochondrial fragmentation
Primary Advisor's Department
Stander Symposium poster
"Drosophila Eye Model to Investigate How Mutations in OPA1 and Drp-1 Genes Contribute to Neurodegeneration in Alzheimer’s Disease" (2018). Stander Symposium Posters. 1151.