Prion Protein Accumulation in Lipid Rafts of Mouse Aging Brain
Prion Protein Accumulation in Lipid Rafts of Mouse Aging Brain
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DOI：
10.1371/journal.pone.0074244
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发表时间：
2013-09-10
期刊：
影响因子：
3.7
通讯作者：
Legname, Giuseppe
中科院分区：
文献类型：
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作者：
Agostini, Federica;Dotti, Carlos G.;Legname, Giuseppe
朊病毒蛋白（PrPC）的细胞形式是神经元细胞膜的正常成分。蛋白质错误折叠导致罕见的神经退行性疾病，称为传染性海绵状脑病或朊病毒病。这些疾病可以是散发性的、遗传性的或传染性的。散发性朊病毒病是最常见的形式，主要影响老年人。在这项工作中，我们研究了散发性朊病毒疾病可能发展的生化环境，将注意力集中在衰老大脑中神经元的细胞膜上。众所周知，随着年龄的增长，筏中最丰富的脂质成分之间的比例发生了重大变化：胆固醇减少，鞘磷脂含量上升。我们的研究结果表明，老化过程修改的PrPC的区室化。在老年小鼠中，这种变化有利于PrPC在耐洗涤剂膜中的积累，特别是在大肠杆菌中。为了确认脂质含量变化和PrPC易位到洗涤剂抗性膜（DRM）之间的关系，我们研究了酸性鞘磷脂酶（ASM）基因敲除（KO）小鼠和富含鞘磷脂的突触体中PrPC的区室化。在高鞘磷脂含量的存在下，我们观察到DRMS中PrPC的显着增加。这一过程不是由于较高水平的总蛋白，它可能反过来，有利于发病的散发性朊病毒疾病在衰老过程中，因为它增加了PrP分子间接触到脂筏。我们观察到，通过使用伏马菌素B1降低痒病感染细胞中的鞘磷脂导致蛋白酶抗性PrP形成减少50%。这可能表明朊病毒形成中PrP脂质环境的参与，因此它可能在散发形式的朊病毒疾病的发病或发展中发挥作用。
The cellular form of the prion protein (PrPC) is a normal constituent of neuronal cell membranes. The protein misfolding causes rare neurodegenerative disorders known as transmissible spongiform encephalopathies or prion diseases. These maladies can be sporadic, genetic or infectious. Sporadic prion diseases are the most common form mainly affecting aging people. In this work, we investigate the biochemical environment in which sporadic prion diseases may develop, focusing our attention on the cell membrane of neurons in the aging brain. It is well established that with aging the ratio between the most abundant lipid components of rafts undergoes a major change: while cholesterol decreases, sphingomyelin content rises. Our results indicate that the aging process modifies the compartmentalization of PrPC. In old mice, this change favors PrPC accumulation in detergent-resistant membranes, particularly in hippocampi. To confirm the relationship between lipid content changes and PrPC translocation into detergent-resistant membranes (DRMs), we looked at PrPC compartmentalization in hippocampi from acid sphingomyelinase (ASM) knockout (KO) mice and synaptosomes enriched in sphingomyelin. In the presence of high sphingomyelin content, we observed a significant increase of PrPC in DRMS. This process is not due to higher levels of total protein and it could, in turn, favor the onset of sporadic prion diseases during aging as it increases the PrP intermolecular contacts into lipid rafts. We observed that lowering sphingomyelin in scrapie-infected cells by using fumonisin B1 led to a 50% decrease in protease-resistant PrP formation. This may suggest an involvement of PrP lipid environment in prion formation and consequently it may play a role in the onset or development of sporadic forms of prion diseases.