Abstract：
BACKGROUND: Brain injury has been suggested as a risk factor for neurodegenerative diseases. Accordingly, defects in the brain\'s intrinsic capacity to repair injury may result in the accumulation of damage and a progressive loss of brain function. The G2019S (GS) mutation in LRRK2 (leucine rich repeat kinase 2) is the most prevalent genetic alteration in Parkinson\'s disease (PD). Here, we sought to investigate how this LRRK2-GS mutation affects repair of the injured brain.
METHODS: Brain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes.
RESULTS: Damaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains.
CONCLUSIONS: The LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury.
METHODS: Brain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes.
RESULTS: Damaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains.
CONCLUSIONS: The LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury.
摘要：
背景：脑损伤已被认为是神经退行性疾病的危险因素。因此，大脑内在修复损伤能力的缺陷可能导致损伤的累积和脑功能的进行性丧失。LRRK2(富含亮氨酸重复序列激酶2)中的G2019S(GS)突变是帕金森病(PD)中最普遍的遗传改变。这里,我们试图研究这种LRRK2-GS突变如何影响受损大脑的修复.
方法：立体定位注射ATP致脑损伤，与损伤相关的分子模式(DAMP)组件，进入野生型(WT)和LRRK2-GS小鼠的纹状体。LRRK2-GS突变对脑损伤和损伤恢复的影响通过分析神经元的分子和细胞行为来检测,星形胶质细胞,和单核细胞。
结果：受损的神经元表达骨桥蛋白（OPN），与大脑修复有关的因素。ATP诱导的损伤后，单核细胞进入受伤的大脑，通过激活炎性体和随后的焦亡，吞噬受损的神经元并产生含有OPN的外泌体样囊泡（EV）。电动汽车生产后，神经元和星形胶质细胞过程向受伤的核心延伸。在LRRK2-GS小鼠中，与WT小鼠相比，OPN表达和单核细胞焦凋亡降低，导致含OPN的EV释放减少，神经元和星形胶质细胞过程的伸长减弱。此外,从受伤的LRRK2-GS大脑制备的外泌体诱导神经突生长的效率低于受伤的WT大脑。
结论：LRRK2-GS突变通过减少OPN的表达和减少单核细胞释放含OPN的EV来延迟受损大脑的修复。这些发现表明，LRRK2-GS突变可能通过延迟脑损伤的修复来促进PD的发展。
方法：立体定位注射ATP致脑损伤，与损伤相关的分子模式(DAMP)组件，进入野生型(WT)和LRRK2-GS小鼠的纹状体。LRRK2-GS突变对脑损伤和损伤恢复的影响通过分析神经元的分子和细胞行为来检测,星形胶质细胞,和单核细胞。
结果：受损的神经元表达骨桥蛋白（OPN），与大脑修复有关的因素。ATP诱导的损伤后，单核细胞进入受伤的大脑，通过激活炎性体和随后的焦亡，吞噬受损的神经元并产生含有OPN的外泌体样囊泡（EV）。电动汽车生产后，神经元和星形胶质细胞过程向受伤的核心延伸。在LRRK2-GS小鼠中，与WT小鼠相比，OPN表达和单核细胞焦凋亡降低，导致含OPN的EV释放减少，神经元和星形胶质细胞过程的伸长减弱。此外,从受伤的LRRK2-GS大脑制备的外泌体诱导神经突生长的效率低于受伤的WT大脑。
结论：LRRK2-GS突变通过减少OPN的表达和减少单核细胞释放含OPN的EV来延迟受损大脑的修复。这些发现表明，LRRK2-GS突变可能通过延迟脑损伤的修复来促进PD的发展。
