Kaempferol alleviates LD-mitochondrial damage by promoting autophagy: Implications in Parkinson's disease.
Kaempferol alleviates LD-mitochondrial damage by promoting autophagy: Implications in Parkinson's disease.
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山奈酚通过促进自噬减轻 LD 线粒体损伤：对帕金森病的影响
DOI：
10.1016/j.redox.2021.101911
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Sun L
中科院分区：
文献类型：
--
作者：
Han X;Zhao S;Song H;Xu T;Fang Q;Hu G;Sun L
新的证据表明，非预期的脂质滴（LD）沉积和过氧化反应可加速细胞器应激，并在神经退行性疾病（NDD）的发病机制中起着至关重要的作用。在我们以前的研究中，我们证实了山奈酚（Ka），一种天然的黄酮类小分子，表现出对LPS诱导的帕金森病（PD）小鼠的神经保护作用。此外，以往的研究表明，自噬在细胞LD沉积的调节中起着重要作用。在目前的研究中，我们表明，Ka保护TH+神经元的损失和MPTP/p诱导的PD小鼠的行为缺陷，伴随着减少黑质的黑质pars延髓（SNpc）的脂质氧化应激。在培养的神经细胞中，Ka表现出相对安全的浓度范围，并显著抑制MPP+诱导的LD蓄积和细胞凋亡。进一步的研究表明，Ka的保护作用依赖于自噬，特别是脂肪吞噬。重要的是，Ka促进自噬介导溶酶体中的LD降解，然后减轻脂质沉积和过氧化以及由此产生的线粒体损伤，从而减少神经元死亡。此外，AAV-shAtg 5-介导的Atg 5敲低消除了Ka对PD小鼠中脂质氧化的神经保护作用。这项工作表明，Ka通过促进脂肪吞噬抑制脂质过氧化介导的线粒体损伤，从而防止PD中多巴胺能神经元变性，并为PD和相关NDD提供了潜在的新治疗策略。
Emerging evidence indicates that unexpected lipid droplet (LD) deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases (NDDs). In our previous study, we confirmed that kaempferol (Ka), a natural flavonoid small molecule, exhibited neuroprotective effects on mice with LPS-induced Parkinson's disease (PD). In addition, previous studies have shown that autophagy plays an important role in the regulation of cellular LD deposition. In the current study, we showed that Ka protected against TH+ neuronal loss and behavioral deficits in MPTP/p-induced PD mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta (SNpc). In cultured neuronal cells, Ka exhibited a relatively safe concentration range and significantly suppressed LD accumulation and cellular apoptosis induced by MPP+. Further study indicated that the protective effect of Ka was dependent on autophagy, specifically lipophagy. Critically, Ka promoted autophagy to mediate LD degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death. Furthermore, AAV-shAtg5-mediated Atg5 knockdown abolished the neuroprotective effects of Ka against lipid oxidation in PD mice. This work demonstrates that Ka prevents dopaminergic neuronal degeneration in PD via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for PD and related NDDs.
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影响因子：
14.8
作者：
Jackson-Lewis, Vernice;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
3.3
作者：
Parihar, MS;Hemnani, T
通讯作者：
Hemnani, T
影响因子：
24.5
作者：
Morales-Ibanez O;Affò S;Rodrigo-Torres D;Blaya D;Millán C;Coll M;Perea L;Odena G;Knorpp T;Templin MF;Moreno M;Altamirano J;Miquel R;Arroyo V;Ginès P;Caballería J;Sancho-Bru P;Bataller R
通讯作者：
Bataller R
DOI：
10.1126/science.aam9080
发表时间：
2017-09-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burbulla LF;Song P;Mazzulli JR;Zampese E;Wong YC;Jeon S;Santos DP;Blanz J;Obermaier CD;Strojny C;Savas JN;Kiskinis E;Zhuang X;Krüger R;Surmeier DJ;Krainc D
通讯作者：
Krainc D
影响因子：
--
作者：
Lee SJ;Zhang J;Choi AM;Kim HP
通讯作者：
Kim HP