α-突触核蛋白和PINK1表达的改变会减少神经突的长度，并诱导中脑神经元的线粒体裂变和高尔基体碎裂。,Neuroscience Letters

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α-突触核蛋白和PINK1表达的改变会减少神经突的长度，并诱导中脑神经元的线粒体裂变和高尔基体碎裂。
Neuroscience Letters ( IF 2.5 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.neulet.2020.134777
Rachel M Furlong ₁ , Gerard W O'Keeffe ₂ , Cora O'Neill ₃ , Aideen M Sullivan ₂

Affiliation

α-突触核蛋白的积累是帕金森氏病（PD）的病理标志，并与中脑多巴胺能神经元神经突长度的减少和轴突变性有关。SNCA中的突变（编码α-突触核蛋白）和PTEN诱导的假定激酶1（PINK1）中的功能突变丧失导致家族性PD。有必要确定α-突触核蛋白过表达和PINK1缺失引起PD中神经变性的机制。为此，我们采用大鼠腹侧中脑培养物来研究野生型或突变型（A53T）α-突触核蛋白过表达以及PINK1的siRNA敲低对神经突长度以及线粒体和高尔基体完整性的影响。我们发现减少的神经突长度和高尔基片段化和线粒体裂变的水平增加，以响应野生型或突变体α-突触核蛋白的过表达以及对PINK1的抑制。这两个PD风险基因引起的神经突长度减少与高尔基体碎裂和线粒体裂变的增加显着相关。α-突触核蛋白过表达和PINK1组合的组合导致神经突长度的减少和高尔基体碎裂的增加，比任何一种情况都大。这项研究提供了新的证据，表明α-突触核蛋白的过度表达和PINK1缺失会聚，导致中脑神经元的高尔基体碎裂和线粒体裂变明显增加，这与神经突长度的减少有关。

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Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons.

Accumulation of α-synuclein is a pathological hallmark of Parkinson's disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 (PINK1) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.

更新日期：2020-01-21

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