Drosophila Model Of Human Pantothenate Kinase-Associated Neurodegeneration

Pantothenate Kinase-Associated Neurodegenerative disease (PKAN) is a severe autosomal recessive human neurodegenerative disease. The typical clinical features of PKAN syndrome include motor abnormalities, reduced lifespans, iron accumulation and neurological degeneration in globus pallidus. PKAN is caused by mutations in the human pantothenate kinase 2 (PANK2) gene, but the pathological mechanism of PKAN is still unknown. PanK2 is the only mitochondria protein among four members of human PanK family. It is unclear whether the differences exist between mitochondrial and cytosolic PanKs, nor whether the subcellular localization is related to PKAN pathogenesis. Since the PanK2 knock-out mice could not reproduce symptoms of the disease, a new model is necessary for further understanding of the mechenism of PKAN.Unlike human and mouse, Drosophila has only one PanK homologue, Fbl. The fbl mutation causes severe abnomalities to fly. In this study, we establish a Drosophila model for human PKAN by introducing mutated forms of human PanK2 into fbl flies. This model faithfully exhibits many behavioral and pathological features reminiscent of PKAN patients. Using this model, we prove that Fbl is the ortholog of human PanK2, with similar subcellular localizations and biological functions, and their localizations are important for their activities. Furthermore, the severity of the disease is strictly correlated with the level of pantothenate kinase activity in vivo. We also find that the spermatogensis and central nerve system function are the most vulnerale biological processes in animals. Finally, a preliminary drug screen is performed in fbl flies searching for helpful compunds for PKAN patients. Our results indicate that PKAN is reliably due to the reduction of pantothenate kinase activity, but not other functions. PanK2 is not active outside mitochondria, while cytosolic PanKs are not active inside mitochondria. And PanK2 might have the highest pantothenate kinase activity in vivo.Conclusively, in this study, we build up a new animal model for human PKAN disease, and further explore the detailed mechanism and search for potential drugs of Pantothenate Kinase-Associated Neurodegeneration. We hope this work would help us to understand the underline nature of PKAN and could benefit others who also concern this question.