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Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum
Cells ( IF 6 ) Pub Date : 2020-10-14 , DOI: 10.3390/cells9102289
Sanjanie Fernando , Claire Y. Allan , Katelyn Mroczek , Xavier Pearce , Oana Sanislav , Paul R. Fisher , Sarah J. Annesley

Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

中文翻译:

α-突触核蛋白在盘基网柄菌中引起的细胞毒性和线粒体失调

α突触核蛋白已与帕金森氏病(PD)的散发和家族形式相关,并且是路易氏体中含量最高的蛋白质,是帕金森氏病的标志。该蛋白的功能及其毒性的分子机制仍不清楚,但许多研究表明,α-突触核蛋白毒性的机制涉及线粒体功能的改变。在这里,我们在真核细胞盘基网柄菌中表达了人类α-突触核蛋白和两个PD致病的α-突触核蛋白突变蛋白(具有点突变,A53T和C末端20个氨基酸的截短)。线粒体D. discoideum中的线粒体疾病已得到充分研究与哺乳动物不同,线粒体功能障碍会导致明显的缺陷表型。这些缺陷表型是由细胞能量传感器AMP激活的蛋白激酶(AMPK)的长期过度激活引起的。α-突触核蛋白野生型和突变型的表达对细胞有毒,线粒体功能失调。AMPK的下调揭示了AMPK依赖性和非依赖性机制,可以挽救部分缺陷表型,但不是全部。重要的是,我们还表明,α-突触核蛋白的C末端是必需的,并且足以将蛋白质定位到D. discoideum中的细胞皮质。
更新日期:2020-10-14
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