Functional role of cellular prion protein in regulating cell adhesion molecule associated transport systems under physiological and pathophysiological conditions

致病形式的朊蛋白（PrPsc）在海绵状脑病的发生发展中起着至关重要的作用，而细胞形式的PrP （PrPc）对氧化应激、缺氧、缺血、兴奋性毒性或低血糖具有保护作用。PrPc有利于维持神经递质系统，特别是血清素能和多巴胺能系统，这些系统受到PrPsc的负面影响。因此，我们将研究PrPc是否调节色氨酸和酪氨酸的摄取，色氨酸和酪氨酸是5 -羟色胺和多巴胺合成的前体，是情绪稳态中重要的神经递质。由于我们发现PrPc调节了星形胶质细胞对谷氨酸和半胱氨酸的摄取，并且两者都是合成抗氧化剂谷胱甘肽所必需的，我们还想分析PrPc是否调节谷胱甘肽的合成，这对于神经元防御氧化应激（包括脆弱的多巴胺能神经元）是必不可少的，多巴胺能神经元的消除导致帕金森病及其情绪障碍。由于我们的研究结果还表明，PrPc调节星形胶质细胞乳酸的释放——这是一种在应激条件下发挥作用的机制——我们想进一步分析PrPc在氧化应激下调节乳酸从星形胶质细胞转运到神经元中的作用，并提出神经保护分子是否可能通过外泌体从星形胶质细胞转运到神经元的问题，外泌体先前已被证明在神经细胞之间穿梭PrPsc。我们现在建议研究携带prpc的外泌体是否传递有益分子以防止神经元细胞死亡。

The pathogenic form of prion protein (PrPsc) plays a crucial role in the development of spongiform encephalopathies, while the cellular form of PrP (PrPc) has protective functions against oxidative stress, hypoxia, ischemia, excitotoxicity or hypoglycemia. PrPc beneficially sustains neurotransmitter systems, in particular the serotonergic and dopaminergic systems, which are negatively affected by PrPsc. Hence, we will study whether PrPc regulates the uptake of tryptophan and tyrosine which are the precursor for serotonin and dopamine synthesis being important neurotransmitters in emotional homeostasis. Since we showed that PrPc regulates uptake of glutamate and cysteine into astrocytes and since both are required for synthesis of antioxidant glutathione, we also want to analyze whether PrPc regulates glutathione synthesis being essential for the defense of neurons against oxidative stress, including the vulnerable dopaminergic neurons, the abolition of which lead to Parkinson’s disease with its emotional disturbances. Since our results also indicated that PrPc regulates the release of lactate from astrocytes - a mechanism that comes into play under stress conditions - we want to further analyze the role of PrPc in regulating lactate transport from astrocytes to neurons under oxidative stress, with the question whether neuroprotective molecules may be conveyed from astrocytes to neurons via exosomes that have previously been shown to shuttle PrPsc between neural cells. We now propose to investigate whether exosomes PrPc-carrying convey beneficial molecules to prevent neuronal cell death.