<br>锰破坏轴突自噬体的成熟和降解，通过激活 LRRK2 对 Rab10 磷酸化导致小鼠海马突触毒性,Science of the Total Environment

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锰破坏轴突自噬体的成熟和降解，通过激活 LRRK2 对 Rab10 磷酸化导致小鼠海马突触毒性
Science of the Total Environment ( IF 8.2 ) Pub Date : 2024-01-13 , DOI: 10.1016/j.scitotenv.2024.170021
Zhuo Ma ₁ , Kuan Liu ₂ , Rui-Feng Zhang ₂ , Zi-Xin Xie ₂ , Wei Liu ₁ , Bin Xu ₁

Affiliation

锰 (Mn) 过度暴露会通过功能失调的突触小泡 (SV) 的积累诱导海马突触毒性。富含亮氨酸重复激酶 2 (LRRK2) 激酶活性参与调节轴突运输（自噬体成熟）和溶酶体功能。然而，目前尚不清楚锰诱导的突触毒性是否与 LRRK2 介导的轴突运输中自噬体成熟的破坏以及海马神经元溶酶体的损伤有关。在这里，我们在 C57BL/6 小鼠和海马神经元 HT22 细胞中建立了锰中毒模型，以验证 LRRK2 介导的 Rab10 磷酸化在锰诱导的自噬-溶酶体融合功能障碍中的作用。我们的结果证明，Mn 诱导轴突运输紊乱，并且溶酶体损伤与轴突和溶酶体上磷酸 Rab10 募集的增加有关。接下来，我们建立了Lrrk2-KD和LRRK2激酶特异性抑制剂（GNE-0877，GNE）预处理的HT22细胞，分别抑制Lrrk2基因表达和激酶活性。在 Mn 处理的 Lrrk2-KD 或 GNE 预处理的正常神经元中，我们的结果表明，溶酶体 pH 值、完整性和自噬流得到恢复，这表明溶酶体上磷酸化 Rab10 和 JNK 相互作用蛋白 (JIP4) 的水平降低。此外，GNE 预处理可以在体内提供针对锰诱导的突触毒性的保护，突触可塑性和突触损伤的部分恢复证明了这一点。因此，Mn诱导的LRRK2异常激活会影响溶酶体和JIP4对磷酸化Rab10的募集，从而破坏近端轴突自噬体的成熟并导致小鼠海马突触毒性。

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Manganese disrupts the maturation and degradation of axonal autophagosome leading to hippocampal synaptic toxicity in mice via the activation of LRRK2 on phosphorylation of Rab10

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice.

更新日期：2024-01-13

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