Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson's Disease.
Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson's Disease.
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Plin4 依赖性脂滴阻碍 MPTP/p 诱导的帕金森病小鼠模型中的神经元线粒体自噬
DOI：
10.3389/fnins.2018.00397
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发表时间：
2018
影响因子：
4.3
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Han X;Zhu J;Zhang X;Song Q;Ding J;Lu M;Sun S;Hu G
流行病学研究表明，脂质代谢紊乱和线粒体功能障碍与包括帕金森病（PD）在内的神经退行性疾病（NDD）的发病机制密切相关。新出现的证据表明，细胞内脂滴（LD）的沉积参与脂毒性和神经退行性变之前。Perilipin家族成员被认为促进LD运动和细胞信号相互作用。然而，在多巴胺能（DA）神经元中，Perilipin调节的LD沉积和线粒体功能障碍之间的直接相互作用仍然不清楚。在这里，我们证明了一种新的类型的脂质失调参与PD的进展，证明了上调表达的Plin 4（包被蛋白和调节LD），并增加细胞内LD沉积与TH-IR（酪氨酸羟化酶免疫反应）神经元在MPTP/p诱导的PD模型小鼠中脑的损失。此外，体外实验表明，通过下调Plin 4抑制LD储存促进了SH-SY 5 Y细胞的存活。从机制上讲，减少LD储存恢复了自噬，导致线粒体损伤减轻，这反过来又促进了细胞存活。此外，parkin-poly-Ub-p62通路参与了Plin 4/LD诱导的线粒体自噬抑制。这些发现在DA能神经元的原代培养物中得到进一步证实，其中自噬抑制剂治疗显著抵消了Plin 4沉默所赋予的改善。总的来说，这些实验证明功能失调的Plin 4/LD/线粒体自噬轴参与PD病理学，并表明Plin 4-LD作为PD的潜在生物标志物以及治疗策略。
Epidemiological studies have shown that both lipid metabolism disorder and mitochondrial dysfunction are correlated with the pathogenesis of neurodegenerative diseases (NDDs), including Parkinson’s disease (PD). Emerging evidence suggests that deposition of intracellular lipid droplets (LDs) participates in lipotoxicity and precedes neurodegeneration. Perilipin family members were recognized to facilitate LD movement and cellular signaling interactions. However, the direct interaction between Perilipin-regulated LD deposition and mitochondrial dysfunction in dopaminergic (DA) neurons remains obscure. Here, we demonstrate a novel type of lipid dysregulation involved in PD progression as evidenced by upregulated expression of Plin4 (a coating protein and regulator of LDs), and increased intracellular LD deposition that correlated with the loss of TH-ir (Tyrosine hydroxylase-immunoreactive) neurons in the MPTP/p-induced PD model mouse mesencephalon. Further, in vitro experiments showed that inhibition of LD storage by downregulating Plin4 promoted survival of SH-SY5Y cells. Mechanistically, reduced LD storage restored autophagy, leading to alleviation of mitochondrial damage, which in turn promoted cell survival. Moreover, the parkin-poly-Ub-p62 pathway was involved in this Plin4/LD-induced inhibition of mitophagy. These findings were further confirmed in primary cultures of DA-nergic neurons, in which autophagy inhibitor treatment significantly countermanded the ameliorations conferred by Plin4 silencing. Collectively, these experiments demonstrate that a dysfunctional Plin4/LD/mitophagy axis is involved in PD pathology and suggest Plin4-LDs as a potential biomarker as well as therapeutic strategy for PD.
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影响因子：
11.1
作者：
Krahmer, Natalie;Farese, Robert V., Jr.;Walther, Tobias C.
通讯作者：
Walther, Tobias C.
影响因子：
16.2
作者：
Pickrell AM;Youle RJ
通讯作者：
Youle RJ
影响因子：
25.7
作者：
Gan, Lay T.;Van Rooyen, Derrick M.;Farrell, Geoffrey C.
通讯作者：
Farrell, Geoffrey C.
DOI：
10.1134/s207020511805012x
发表时间：
2018-10-10
影响因子：
0.800
作者：
Ph. V. Kiryukhantsev-Korneev;A. N. Sheveiko
通讯作者：
A. N. Sheveiko
影响因子：
64.5
作者：
Bailey AP;Koster G;Guillermier C;Hirst EM;MacRae JI;Lechene CP;Postle AD;Gould AP
通讯作者：
Gould AP