BLEBBISTATIN ALLEVIATED HYPERLOCOMOTION IN A53T Α-SYNUCLEIN PARKINSON’S DISEASE MODEL

초록

Objectives: 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 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. Methods: A53T-α-syn overexpressed transgenic mice (line G2-3) is widely used as a PD animal model (Lee et al., 2002). Mice (7 mo, 12 mo A53T Tg and littermate WT) were administrated with blebbistatin (Bleb, 10 mg/kg, i.p.) daily once for two weeks. Also, we developed the in vitro PD model, A53T overexpression in cultured cortical neuron by adeno associated viral vector system. We investigated how Bleb treatment influences transgenic mouse models by mediating molecular changes in cortex, hippocampus and striatum region using immunohistochemical, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and behavioral analysis. Results: We demonstrated that the treatment of Bleb, a non-muscle myosin II inhibitor, improves mitochondrial dysfunction and hyperlocomotion caused by A53T-α-syn in the in-vitro and in-vivo model. After α-syn overexpression, dynamin-related protein 1 (Drp1, mitochondrial fission marker) level significantly increased in PD model, whereas the elevated Drp1 level was suppressed in the Bleb co-treated groups. Also, Similarly, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α, mitochondrial homeostasis marker) and sirtuin 1 (Sirt-1, mitochondrial homeostasis marker) levels significantly decreased in PD model, whereas the decreased levels were suppressed in the Bleb co-treated groups. The behavioral showed hyperlocomotion in transgenic mice model was rescued by Bleb. Conclusions: Our study reveals that Bleb could play a role in alleviating the symptoms of PD in A53T PD model.