PARK9モデル細胞における細胞内鉄恒常性の破綻を介した細胞傷害の解析

抄録

Parkinson's disease is a neurodegenerative disease characterized by the degeneration of dopamine neurons in the substantia nigra. ATP13A2 has been reported as a causative gene of PARK9. ATP13A2 is a lysosomal localized ATPase and involved in the transport of metal ions such as divalent iron ions (Fe²⁺). In addition, iron accumulation is observed in the brains of PARK9 patients. Therefore, it is considered that ATP13A2 contributes to the maintenance of intracellular iron homeostasis. However, there are still unclear points about the effect of ATP13A2 dysfunction on intracellular iron homeostasis and the mechanism of neurodegeneration. To reveal these issues, a PARK9 model cell was created by ATP13A2 knockdown in SH-SY5Y cells. In addition, their effects on lysosomal function and intracellular iron homeostasis were analyzed. As a result, an increase in oxidative stress and a decrease in cell viability were observed in PARK9 model cell. In addition, autophagy markers and α-synuclein were increased in PARK9 model cell, suggested that ATP13A2 knockdown induced autophagy dysfunction. Moreover, accumulation of Fe²⁺ in lysosomes and mitochondria was confirmed by fluorescent probes in PARK9 model cell, indicating that ATP13A2 knockdown caused the disruption of intracellular iron homeostasis. These results contribute to reveal the pathophysiology of Parkinson's disease and diseases related to iron deposition.