目前α-synuclein(α-syn)突变体导致的PD发病机制已十分明了，但人们对α-syn突变体的上游调控蛋白却知之甚少。近年来研究表明丝氨酸蛋白酶Omi/HtrA2在某些体细胞及神经前体细胞内可诱导自噬，并负向调节α-syn突变体的含量。鉴于PD受损细胞的特殊性，Omi能否在多巴胺神经元内诱导自噬并调节α-syn突变体含量还有待研究。本研究在前期工作的基础上, 采用外源性转染、药物诱导及原代培养等技术获得多巴胺神经元，并建立PD细胞模型；通过过表达、siRNA及免疫印迹等技术揭示Omi在PD模型细胞内诱导自噬减少α-syn突变体（A53T）的机制。揭示α-syn突变体的调控蛋白及调控机制，将为进一步了解PD的发病原因、研发PD治疗方法及特效药物提供依据。

Many previously studies proved that α-synuclein (α-syn) mutants play a crucial role in pathogenesis of PD. However regulatory proteins of alpha -syn mutants are remain largely unknown. Recent studies showed that the serine protease HtrA2/Omi induces autophagy in certein somatic cells and neural precursor cells and negatively regulates the levels of α-syn mutants. Alpha-syns distribute mainly in presynapse, also distribute in myocardial cells and muscle tissue. Interestingly, Omi acts as an apoptotic inducing protein in non-neuronal somatic cell under the stress and acts as a neuronal protective factor in neurons. Because of the dual functions of Omi in defferent cell type, it is necessary to indicate that Omi whether induces autophagy in neurons and downregulates the α-syn mutants. This study base on previous works, transfection, induction and primary culture techniques will be used to obtain dopaminergic neurons and establish the PD model. Overexpression , siRNA knockdown and western blot techniques will be used to reveal that Omi induce autophagy in dopaminergic neurons and downregulate the α-synA53T mutant in PD model. Revealing the regulatory proteins of α-syn mutants will be usful to futher understand pathogenesis of PD, and also usful to develop new drug to treat PD.

目前α-synuclein(α-syn)突变体导致的PD发病机制已十分明了，但人们对α-syn突变体的上游调控蛋白却知之甚少。近年来研究表明丝氨酸蛋白酶Omi/HtrA2在某些体细胞及神经前体细胞内可诱导自噬，并负向调节α-syn突变体的含量。鉴于PD受损细胞的特殊性，Omi能否在多巴胺神经细胞内诱导自噬并调节α-syn突变体含量还有待研究。现阶段完成dbcAMP诱导N2a获得多巴胺神经元，转染过表达Omi（WT/MT），利用自噬标志蛋白LC3抗体观察自噬增加，发现过表达Omi后α-syn A53T的寡聚体减少，当siRNA抑制Omi表达，α-syn A53T的寡聚体增加。