Stress Response in a Novel Drosophila Model of Neurodegenerative diseases ALS and Glaucoma
While I am observing morphological changes due to neurodegeneration in the mouse study described above, I am simultaneously observing behavioral changes related to neurodegeneration in a Drosophila study. In this research project, I use genetically engineered Drosophila models with mutations in a gene related to glaucoma and amyotrophic lateral sclerosis (ALS). The protein created from this gene, optineurin (OPTN), is linked to many cellular functions including protein trafficking, ubiquitin-binding, and autophagy. In humans, mutated OPTN has been shown to cause degeneration of retinal and motor neurons prompting debilitating diseases such as glaucoma and ALS. I observe these novel OPTN Drosophila models to investigate the effects of OPTN and three of its mutations on cellular stress, locomotion, and survival of Drosophila melanogaster. Additionally, I am able to express these mutant OPTN proteins in specific parts of the fly, including motor neurons, all neurons, or glial cells. Correlating different phenotypic behaviors with protein expression of different mutant OPTN separately in different cells gives us insight on the roles of different types of cells during the progression of each disease.
Results show an age-related degeneration mechanism through the mortality rate of Drosophila expressing the ALS mutation in all neurons and in glial cells. Interestingly, the glaucoma mutation showed no adverse effects on the fly lifespan when expressed in any cell type, and in fact decreased fly mortality when expressed in glial cells. Lack of impact on survival is consistent with the phenotype in human glaucoma patients. Climbing assays showed that expression of mutant OPTN transgenes impaired fly locomotion in general. Additionally, a sudden increase in stress response was seen in the glial cells of flies expressing the ALS mutation at week 5, and may suggest that glial cell stress dominates in the development of ALS.
From a clinical standpoint, the discovery of specific pathways that lead to neuronal death in glaucoma and ALS are key in developing successful treatments and preventative care. Insight gained from mutant OPTN fly models of ALS, including disease development time course and detrimental effects in the glia, may have important clinical implications that guide the development and treatment of drugs for this disease. Similarly, an understanding of the time course and direct neurodegenerative effects of the expression of the glaucoma OPTN mutant in neurons may be helpful for therapeutic strategies that target the neurons directly.
Project duration: Aug. 2016 – May 2017; Aug. 2017 – Present
Weekly hours: 10
Total hours expected: 500
Supervisor: Dr. Henry Tseng (firstname.lastname@example.org)