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.

富含亮氨酸的重复激酶 2 (LRRK2) 基因突变是常染色体显性遗传帕金森病 (PD) 的最常见原因，会产生精神和运动症状。我们进行了这项研究，通过采用年轻和中年 PD 模型小鼠来探索小胶质细胞多巴胺能 (DAergic) 纤维细化和突触修剪是否与 LRRK2 G2019S 突变携带者的异常行为表型有关。结果揭示了 LRRK2 G2019S 突变小鼠的特征性迟发性多动症和运动协调性逐渐下降。LRRK2 G2019S 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 (DAergic) 纤维过度细化小胶质细胞。而且，异常突触修剪明显影响前额叶皮层 (PFC) 和背侧纹状体 (DS)，PFC 的脊柱密度显着增加，但 DS 区域的效果相反。此外，LRRK2 G2019S 突变重塑了小胶质细胞的炎症转录环境，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 突变诱导炎性细胞因子的产生并介导异常的小胶质细胞形态发生和活性，导致衰老过程中吞噬作用异常、突触修剪和 DAergic 纤维丢失，最终导致 PD 相关的行为异常。LRRK2 G2019S 突变重塑了小胶质细胞的炎症转录环境，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 突变诱导炎性细胞因子的产生并介导异常的小胶质细胞形态发生和活性，导致衰老过程中吞噬作用异常、突触修剪和 DAergic 纤维丢失，最终导致 PD 相关的行为异常。LRRK2 G2019S 突变重塑了小胶质细胞的炎症转录环境，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 突变诱导炎性细胞因子的产生并介导异常的小胶质细胞形态发生和活性，导致衰老过程中吞噬作用异常、突触修剪和 DAergic 纤维丢失，最终导致 PD 相关的行为异常。