Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors
Age-related LRRK2 G2019S Mutation Impacts Microglial Dopaminergic Fiber Refinement and Synaptic Pruning Involved in Abnormal Behaviors
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与年龄相关的 LRRK2 G2019S 突变影响小胶质细胞多巴胺能纤维细化和参与异常行为的突触修剪
DOI：
10.1007/s12031-021-01896-6
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发表时间：
2021-08-19
影响因子：
3.1
通讯作者：
Pan, Xiaodong
中科院分区：
文献类型：
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作者：
Zhang, Qiuyang;Cheng, Xiaojuan;Pan, Xiaodong
富含亮氨酸重复序列激酶2（LRRK2）基因突变是常染色体显性帕金森病（PD）的最常见原因，可产生精神和运动症状。本研究采用年轻和中年PD模型小鼠，探讨小胶质细胞多巴胺能（DA能）纤维细化和突触修剪是否参与LRRK2 G2019S突变携带者的异常行为表型。结果显示，LRRK2 G2019S突变小鼠的特征性迟发性多动症和运动协调性进行性下降。LRRK2 G2019 S突变诱导的异常小胶质细胞形态发生，每个细胞具有更多的分支和连接，导致多巴胺能（DA能）纤维的过度小胶质细胞细化。此外，异常的突触修剪明显影响了前额叶皮层（PFC）和背侧纹状体（DS），PFC中的棘密度显着较高，但在DS区域的相反的效果。此外，LRRK2 G2019S突变重塑了小胶质细胞的炎症转录景观，使某些大脑区域对小胶质细胞免疫反应高度敏感。这些发现表明，LRRK2 G2019S突变诱导产生炎性细胞因子，介导异常的小胶质细胞形态发生和活性，导致异常的吞噬作用，突触修剪和DA能纤维在衰老过程中的损失，并最终导致PD相关的行为异常。
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of autosomal dominant Parkinson's disease (PD), producing psychiatric and motor symptoms. We conducted this study to explore whether microglial dopaminergic (DAergic) fiber refinement and synaptic pruning are involved in the abnormal behavioral phenotypes of carriers of the LRRK2 G2019S mutation, by employing young and middle-aged PD model mice. The results revealed a characteristic late-onset hyperactivity and a progressive decline in the motor coordination of the LRRK2 G2019S mutation mice. LRRK2 G2019S mutation-induced aberrant microglial morphogenesis, with more branches and junctions per cell, resulted in excessive microglial refinement of dopaminergic (DAergic) fibers. Moreover, aberrant synaptic pruning distinctly impacted the prefrontal cortex (PFC) and dorsal striatum (DS), with significantly higher spine density in the PFC but the opposite effects in the DS region. Furthermore, LRRK2 G2019S mutation remodeled the inflammatory transcription landscape of microglia, rendering certain cerebral areas highly susceptible to microglial immune response. These findings indicate that LRRK2 G2019S mutation induces the production of inflammatory cytokines and mediates abnormal microglial morphogenesis and activity, resulting in abnormal phagocytosis, synaptic pruning and loss of DAergic fibers during aging, and, eventually, PD-related behavioral abnormalities.