Blebbistatin alleviates mitochondrial dysfunction and hyperlocomotion in mutant A53T α-synuclein Parkinson’s disease animal model

초록

Parkinson’s disease (PD) is a common neurodegenerative disorder associated with misfolding and aggregation of α-synuclein protein (α-syn). Recently, it has been strongly suggested that A53T mutated α-syn represents the different phenotype of the age-dependent PD model. However, it is still unclear how different effects of each period induced by A53T mutated α-syn involve neurodegeneration and whether targeting this pathway has therapeutic potential. Overexpression of α-syn was shown cortex, hippocampus, and striatum region in the in-vivo and in-vitro model. Here, we found that the treatment of blebbistatin (Bleb), a non-muscle myosin II inhibitor, reduces the accumulation of α-syn in cultured neuron and transgenic mouse models induced by the A53T mutated α-syn (G2-3 mouse). In the cultured cells infected with AAV-A53T-α-syn, Bleb reduced α-syn accumulation and neuroinflammatory response and protected neuronal damage, regulating mitochondrial dynamics. In the transgenic mice overexpressed A53T-α-syn, Bleb reduced accumulation of α-syn, inhibited gliosis in the cortex, rescued mitochondrial dysfunction and improved behavioral performance in the early-stage of PD model (7-month old Tg) but, not in 12-month PD model. These findings indicate that Bleb attenuates the α-syn accumulation and gliosis by preventing mitochondrial dysfunction and may be a potential target for alleviating hyperlocomotion in A53T early-stage PD model.