Investigation of the role of OPA1 and Drp1 gene mutations in amyloid-beta 42 mediated neurodegeneration in Alzheimer’s Disease
Elizabeth Ann Borchers, Neha Gogia
Alzheimer’s Disease (AD), is a progressive neurodegenerative disorder with no known cure to-date. This disease is caused by extra-cellular accumulation of amyloid-beta 42 (Aβ42) plaques, which results in neuronal cell death. As the genetic machinery is conserved between fruit flies and humans, in this study, we have used Drosophila melanogaster (a.k.a fruit fly) as our model organism and Drosophila eye as our model organ. We have developed a transgenic Drosophila model of AD where using GAL4/UAS system, the human Aβ42 peptides are misexpressed specifically in the differentiating photoreceptor neurons of the fly eye, resulting in death of these neurons without affecting the reproductive ability and life span of the flies. One of the hallmarks of AD is the generation of reactive oxygen species (ROS) from mitochondria, which triggers neuronal cell death. We hypothesize that 1. OPA1 (Mitochondrial Dynamin Like GTPase), and 2. Drp1 (dynamin related protein-1), (conserved between flies and humans), regulate mitochondrial fusion and fission respectively, are involved in regulating Aβ42 mediated neurodegeneration. A fine balance between mitochondrial fission and fusion events is essential for normal mitochondrial and cellular function and it has been known that mutations of OPA1 (an early stop signal) produce small unstable mitochondrial proteins, which increase ROS levels in the neurons. There is a strong correlation between increased ROS levels and mitochondrial fragmentation with neuronal death. Thus, we investigate the role of both OPA1 and Drp1 in Aβ42 mediated neurodegeneration. Results from our preliminary data show that up-regulation of OPA1 in Aβ42 background, significantly rescued Aβ42 mediated neurodegeneration only in female flies, and down-regulating OPA1 rescued Aβ42 neurodegeneration only in male flies. In contrast, down-regulating Drp1, rescued Aβ42 mediated neurodegeneration only in female flies, while up-regulation of Drp1 did not produce any rescues. Further studies on how mitochondrial maternal inheritance takes place will help us better understand these results.
Primary Advisor's Department
Stander Symposium project
"Investigation of the role of OPA1 and Drp1 gene mutations in amyloid-beta 42 mediated neurodegeneration in Alzheimer’s Disease" (2019). Stander Symposium Projects. 1497.