Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation.
Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation.
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神经元 SH2B1 通过促进 PLIN4 降解来减弱帕金森病 MPTP 小鼠模型中的细胞凋亡
DOI：
10.1016/j.redox.2022.102308
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Han X;Liu Y;Dai Y;Xu T;Hu Q;Yi X;Rui L;Hu G;Hu J
帕金森病（PD）的发病率急剧增加，特别是在老年人群和代谢功能障碍人群中；然而，其潜在的分子机制尚不清楚。SH2B1是一种细胞内接头蛋白，参与多种受体酪氨酸激酶的信号转导，对体重调节有有益的代谢作用；然而，SH2B1是否在PD的病理性神经变性中起主要作用尚未被研究。本研究旨在探讨SH2B1对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的SH2B1缺乏或神经元特异性SH2B1过表达的PD小鼠的影响。通过对人多巴胺能神经元SH-SY5Y细胞的分析，阐明了细胞和分子机制。我们发现SH2B1的表达在PD患者的血液样本和mptp诱导的慢性PD小鼠的大脑中被证实下调。在mptp处理的小鼠中，Sh2b1缺乏引起行为缺陷的显著加剧和神经元凋亡的增加，而恢复神经元特异性Sh2b1表达可显著逆转这些影响。在MPP +处理的SH-SY5Y细胞中观察到类似的结果。机制上，通过与热休克同源物70 （HSC70）结合，SH2B1促进HSC70相关识别和PLIN4溶酶体易位和降解，从而抑制PD小鼠脑内脂质过氧化应激。腺相关病毒介导的神经元HSC70表达的修复在功能上减轻了野生型PD的神经病理，但在sh2b1缺陷小鼠中没有。这是第一个在体内PD模型中通过细胞自主促进神经元存活来检测SH2B1抗mptp诱导的神经变性的分子基础的研究。我们的研究结果表明，SH2B1通过SH2B1 - hsc70 - plin4轴拮抗PD的神经退行性病理。PD小鼠脑组织，尤其是TH+神经元中SH2B1表达水平较低。SH2B1通过抑制神经元凋亡抑制mptp诱导的神经退行性变。SH2B1过表达可通过HSC70保护MPP +诱导的细胞死亡。SH2B1与HSC70相互作用形成调节PLIN4降解的复合物。
The incidence of Parkinson's disease (PD) has increased tremendously, especially in the aged population and people with metabolic dysfunction; however, its underlying molecular mechanisms remain unclear. SH2B1, an intracellular adaptor protein, contributes to the signal transduction of several receptor tyrosine kinases and exerts beneficial metabolic effects for body weight regulation; however, whether SH2B1 plays a major role in pathological neurodegeneration in PD has not yet been investigated. This study aimed to investigate the effects of SH2B1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD mice with Sh2b1 deficiency or neuron-specific Sh2b1 overexpression. Cellular and molecular mechanisms were elucidated using human dopaminergic neuron SH-SY5Y cells analysed. We found that SH2B1 expression was confirmed to be downregulated in the blood samples of PD patients and in the brains of mice with MPTP-induced chronic PD. Sh2b1 deficiency caused marked exacerbation of behavioural defects and increased neuronal apoptosis in MPTP-treated mice, whereas restoration of neuron-specific Sh2b1 expression significantly reversed these effects. Similar results were observed in MPP + -treated SH-SY5Y cells. Mechanistically, upon binding to heat shock cognate 70 (HSC70), SH2B1 promotes HSC70-related recognition and PLIN4 lysosomal translocation and degradation, thus suppressing lipid peroxidation stress in the brains of PD mice. Adeno-associated virus-mediated rescue of neuronal HSC70 expression functionally alleviated the neuropathology of PD in wild-type but not in Sh2b1-deficient mice. This is the first study to examine the molecular underpinnings of SH2B1 against MPTP-induced neurodegeneration through cell autonomous promotion of neuronal survival in an in vivo PD model. Our findings reveal that SH2B1 antagonizes neurodegenerative pathology in PD via the SH2B1–HSC70–PLIN4 axis. Brain tissues, especially in TH+ neurons, of PD mice showed low SH2B1 expression. SH2B1 suppressed MPTP-induced neurodegeneration by inhibiting neuronal apoptosis. SH2B1 overexpression protected against MPP + -induced cell death via HSC70. SH2B1 interacts with HSC70 to form a complex that regulates PLIN4 degradation.
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DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
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