Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK.
Neuropharmacology. 2011 Feb-Mar;60(2-3):365-72. doi: 10.1016/j.neuropharm.2010.10.001. Epub 2010 Oct 8.
The prion diseases are characterised by the formation of the disease-associated isoform of the prion protein (PrP(Sc)) and the production of disease-related peptides. The prion derived peptide PrP82-146 bound readily to cortical neurons and was found within detergent resistant membranes that are commonly called lipid rafts. It was not found within lysosomes and the slow degradation of PrP82-146 resulted in a half-life of approximately 5 days. In cortical neurons pre-treated with phospholipase A(2) (PLA(2)) inhibitors (AACOCF(3) or MAFP) less PrP82-146 entered lipid rafts, more PrP82-146 was found within lysosomes and the half-life of PrP82-146 was reduced to 24 h. Similarly, pre-treatment of neurons with platelet-activating factor (PAF) receptor antagonists (Hexa-PAF and ginkgolide B) increased the entry of PrP82-146 into lysosomes and reduced its half-life. Furthermore, the addition of PAF reversed the effects of PLA(2) inhibitors on PrP82-146 trafficking. PAF controlled the amount of cholesterol in cell membranes and the effects of PAF receptor antagonists on the trafficking of PrP82-146 were reversed by the addition of cholesterol. We conclude that activation of PLA(2) and the production of PAF control a cholesterol-sensitive pathway that affects the cellular localisation and hence the fate of PrP82-146 in neurons.
朊病毒疾病的特征是形成疾病相关的朊病毒蛋白（PrP(Sc)）异构体和产生疾病相关肽。朊病毒衍生肽 PrP82-146 容易结合皮质神经元，并存在通常称为脂筏的去污剂抗性膜内。它不在溶酶体内，PrP82-146 的缓慢降解导致半衰期约为 5 天。在预先用磷脂酶 A(2)（PLA(2)）抑制剂（AACOCF(3)或 MAFP）处理的皮质神经元中，进入脂筏的 PrP82-146 减少，更多的 PrP82-146 在溶酶体内，PrP82-146 的半衰期缩短至 24 小时。类似地，用血小板激活因子 (PAF) 受体拮抗剂（Hexa-PAF 和银杏内酯 B）预处理神经元会增加 PrP82-146 进入溶酶体的数量并缩短其半衰期。此外，PAF 的添加逆转了 PLA(2)抑制剂对 PrP82-146 转运的影响。PAF 控制细胞膜中的胆固醇含量，并且 PAF 受体拮抗剂对 PrP82-146 转运的影响可以通过添加胆固醇来逆转。我们得出结论，PLA(2)的激活和 PAF 的产生控制着影响 PrP82-146 在神经元中细胞定位和命运的胆固醇敏感途径。
