Zhu Zhou-Jing, Wu Ka-Chun, Yung Wing-Ho, Qian Zhong-Ming, Ke Ya
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, NT, Hong Kong.
Laboratory of Neuropharmacology, Fudan University School of Pharmacy, 826 Zhang Heng Road, Pu Dong, Shanghai 201203, China.
Biochim Biophys Acta. 2016 Apr;1862(4):518-525. doi: 10.1016/j.bbadis.2016.01.002. Epub 2016 Jan 6.
Alpha-synuclein aggregation is the central hallmark of both sporadic and familial Parkinson's disease (PD). Patients with different PD-causing genetic defects of alpha-synuclein usually show distinctive clinical features that are atypical to sporadic PD. Iron accumulation is invariably found in PD. Recent studies showed that mutant and wild-type alpha-synuclein may have differential interaction with iron and mutant alpha-synuclein toxicity could be preferentially exacerbated by iron. We hence hypothesized that iron overload could selectively influence mutant alpha-synuclein toxicity and disease phenotypes. To test the hypothesis, we investigated if Drosophila melanogaster over-expressing A53T, A30P, and wild-type (WT) alpha-synuclein have different responses to iron treatment. We showed that iron treatment induced similar reduction of survival rate in all flies but induced a more severe motor decline in A53T and A30P mutant alpha-synuclein expressing flies, suggesting interaction between mutant alpha-synuclein and iron. Although no significant difference in total head iron content was found among these flies, we demonstrated that iron treatment induced selective DA neuron loss in motor-related PPM3 cluster only in the flies that express A53T and A30P mutant alpha-synuclein. We provided the first in vivo evidence that iron overload could induce distinctive neuropathology and disease phenotypes in mutant but not WT alpha-synuclein expressing flies, providing insights to the cause of clinical features selectively exhibited by mutant alpha-synuclein carriers.
α-突触核蛋白聚集是散发性和家族性帕金森病（PD）的核心特征。携带不同导致PD的α-突触核蛋白基因缺陷的患者通常表现出与散发性PD不同的独特临床特征。在PD中总是发现铁蓄积。最近的研究表明，突变型和野生型α-突触核蛋白可能与铁有不同的相互作用，并且铁可能会优先加剧突变型α-突触核蛋白的毒性。因此，我们假设铁过载可能会选择性地影响突变型α-突触核蛋白的毒性和疾病表型。为了验证这一假设，我们研究了过表达A53T、A30P和野生型（WT）α-突触核蛋白的黑腹果蝇对铁处理是否有不同反应。我们发现，铁处理导致所有果蝇的存活率都有类似程度的降低，但在表达A53T和A30P突变型α-突触核蛋白的果蝇中诱导了更严重的运动功能衰退，这表明突变型α-突触核蛋白与铁之间存在相互作用。尽管在这些果蝇之间未发现总头部铁含量有显著差异，但我们证明，铁处理仅在表达A53T和A30P突变型α-突触核蛋白的果蝇中诱导运动相关的PPM3簇中的多巴胺能神经元选择性丢失。我们提供了首个体内证据，表明铁过载可在表达突变型而非野生型α-突触核蛋白的果蝇中诱导独特的神经病理学和疾病表型，这为突变型α-突触核蛋白携带者选择性表现出的临床特征的病因提供了见解。
