蛋白转运异常和自噬受损在帕金森病PD发病中起着重要作用，但具体机制尚待阐明。RAB39B位于X染色体，属于参与蛋白转运的RAB GTPase基因家族成员，但功能未知。最近发现RAB39B的功能缺失突变会导致X染色体相关的PD和智力障碍。在此，我们将利用构建好的Rab39b敲除小鼠，聚焦探讨RAB39B缺失在PD过程中的功能作用。包括在细胞水平上研究RAB39B的缺失以及过表达对于神经元形态和功能的影响、对于多巴胺受体的转运及其信号通路的干扰、以及对于自噬特别是alpha-synuclein的自噬降解和线粒体自噬的影响；在动物水平上研究Rab39b敲除小鼠自身的PD相关行为异常和病理变化、探讨Rab39b缺失是否参与MPTP诱导的PD症状以及在alpha-synuclein转基因小鼠中恶化alpha-synuclein病理症状和动物行为异常。研究结果将确定RAB39B突变导致PD的分子机制。

Both protein trafficking dysregulation and autophagy impairment play important roles in the pathogenesis and development of Parkinson’s disease (PD). But the detailed mechanism has yet to be completely elucidated. The RAB39B gene locates on X chromosome and belongs to the RAB GTPase gene family that encodes proteins important for protein trafficking regulation. However, the function of RAB39B remains elusive. Recently it has been found that loss-of-function mutations in the RAB39B gene can cause X chromosome-linked PD as well as intellectual disability. Herein, we will focus on the mechanism underlying RAB39B deficiency-caused PD. At cellular level, we will investigate the effects of RAB39B deficiency and overexpression on neuron morphology and function, on protein trafficking and downstream signaling pathways of dopamine receptors, and on autophagy, especially autophagy that degrades alpha-synuclein and mitochondrial autophagy (mitophagy). Moreover, we will determine PD-related pathologies and behaviors in Rab39b knockout (KO) mice that we generated recently. We will challenge these mice with MPTP to study whether RAB39B is required for MPTP-induced PD-related pathologies and behaviors. Finally, we will cross Rab39b KO mice with alpha-synuclein transgenic mice to study whether RAB39B deficiency deteriorate alpha-synuclein pathologies and PD-related behaviors in alpha-synuclein transgenic mice. These studies shall reveal the mechanism underlying RAB39B mutation-induced disease pathogenesis, providing insight into PD treatment strategies targeting RAB39B.