CoEN 4007- Is prion like propagation of alpha synuclein aggregation associated with a ferroptotic cell death

该项目提出了一项创新的研究，可以迅速导致对帕金森病的神经保护治疗，帕金森病是一种影响我们老龄化人口中数百万人的疾病。目前可用的药物试图只治疗疾病症状，而不是病因。我们的项目基于最近的发现，这两个主要特征涉及大脑中分泌多巴胺神经递质的专门神经元的靶向死亡。第一种是一种叫做α-突触核蛋白的蛋白质的异常聚集，这种蛋白质在大脑中逐渐扩散，与多巴胺能细胞死亡有关。第二种是我们在多巴胺能神经元中观察到的一种新发现的细胞死亡途径，称为铁凋亡。α-突触核蛋白参与细胞铁平衡，其聚集状态因铁的存在而改变，铁凋亡是一个铁依赖的过程。因此，本项目提出阐明α-在帕金森病中观察到的突触核蛋白可以促进铁凋亡，从而加剧整个大脑神经元死亡的扩散。

This project proposes an innovative study that could rapidly lead to neuroprotective treatmentsagainst Parkinson's disease, a disorder that affects millions of people within our ageing population.Current available drugs attempt to only treat the disease symptoms not its etiology. We base ourproject upon recent findings concerning two main features involved in the targeted death ofspecialized neurons in the brain that secrete a neurotransmitter called dopamine. The first is theabnormal aggregation of a protein called alpha-synuclein that progressively spreads throughout thebrain in correlation with the dopaminergic cell death. The second is the involvement of a newlydiscovered pathway of cell death that we have observed in dopaminergic neurons called ferroptosis.Both phenomena are related with iron; alpha-synuclein is involved in cellular iron balance with itsaggregation state modified by the presence of iron, and ferroptosis is an iron dependent process.Thus this project proposes to elucidate how the modifications to alpha-synuclein observed in Parkinson'sdisease can promote ferroptosis to exacerbate the spreading of neuron death throughout the brain.Outcomes expected from this work are innovative therapeutic strategies based upon recentlygenerated anti-ferroptotic drugs.