Understanding The Molecular Basis Of Two Neurodegenerative Diseases Using Drosophila Model

Neurodegenerative diseases are increasingly impacting human health, including Alzheimer’s Disease, Parkinson’s Disease, Huntington disease, fragile X-associate tremor/ataxia syndrome. It has been shown that epigenetic modulation, including environment could impact the disease phenotype or onset. In order to identify the genes involved in the pathogenesis of neurodegenerative disorders, we utilized classic animal model-Drosophila melanogaster, which has many advantages like fewer chromosomes than mammalian animals, highly conserved homologous genes to mammalian genome, signal pathway, progeny production obey Mendelian laws of inheritance, as well as numerous genetic mutants available. We focused on disease mechanisms two neurodegenerative diseases, FXTAS and Alzheimer’s disease.Although the etiology of Fragile X-associated tremor/ataxia(FXTAS) and Alzheimer’s disease are unclear, there are several mechanisms that have been proposed. In FXTAS, such as the sequestration of specific RNA protein, RAN translation, R-Loop, down-regulation of FMRP. In Alzheimer’s disease, the accumulation of beta-amyloid hypothesis and Tau protein abnormalities could be involved in disesase pathogenesis.Purine-rich element-binding protein A(Pur-alpha) plays a crucial role in brain development and also known to regulate DNA replication, transcription and translation. Pur-alpha has been demonstrated to have crucial role in the etiology in FXTAS, but the biological significance of Pur-alpha activity was unknown. To address this question, we took the structure biology approach to determine the structure of mutant DNA- and RNA-binding domains of Pur-alpha to investigate the binding mechanism, and then utilized transgene fly to determine its functional relevance in vivo. It has been well established that DNA methylation could be involved in gene regulation.Existing DNA modifications include adenine methylation and cytosine methylation which includes 5m C, 5hm C, 5f C, 5ca C. It has been shown that 5hm C is altered in FXTAS, so we want to investigate whether 5hm C is altered in Alzheimer’s disease, Genome-wide profiling led us to identify several candidate genes with altered 5hm C that could contribute to the pathogenesis of Alzheimer’s disease, which were further tested using AD fly model. We identified nine epigenetic modifiers of AD through our effort.In summary. By integrating structural biology, genome-wide epigenetic profiling and fly genetics, my works provide new insight into the disease pathogenesis of neurodegenerative disorders.