Polar substitutions in helix 3 of the prion protein produce transmembrane isoforms that disturb vesicle trafficking.
Polar substitutions in helix 3 of the prion protein produce transmembrane isoforms that disturb vesicle trafficking.
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DOI：
10.1093/hmg/ddt276
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发表时间：
2013-11
影响因子：
3.5
通讯作者：
J. Sanchez-Garcia;Daniela Arbeláez;K. Jensen;D. Rincon-Limas;P. Fernandez-Funez
中科院分区：
文献类型：
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作者：
J. Sanchez-Garcia;Daniela Arbeláez;K. Jensen;D. Rincon-Limas;P. Fernandez-Funez
朊病毒疾病包括一组不同的神经退行性疾病，其特征在于错误折叠的朊病毒蛋白（PrP）亚型的积累。也有人提出PrP的其他构象变体有助于朊病毒疾病中的神经毒性，包括错误折叠的中间体以及胞质和跨膜同种型。为了更好地了解PrP神经毒性，我们分析了螺旋3中两个高度保守的甲硫氨酸对PrP生物发生、折叠和发病机制的作用。PrP-M205 S和-M205，212 S突变体在果蝇中的表达导致高糖基化，细胞内积累和广泛的构象变化，由于氧化折叠的失败。令人惊讶的是，PrP-M205 S和-M205，212 S获得了先前与信号肽（SP）和跨膜结构域（TMD）中的突变相关的跨膜拓扑结构（Ctm）。PrP-M205，212 S还破坏了脂筏中关键神经发育蛋白的积累，导致轴突投射缩短。这些结果揭示了一个新的作用的疏水结构域，促进氧化折叠和防止形成神经毒性的CTM PrP，机制可能是相关的遗传性和散发性朊病毒疾病的发病机制。
Prion diseases encompass a diverse group of neurodegenerative conditions characterized by the accumulation of misfolded prion protein (PrP) isoforms. Other conformational variants of PrP have also been proposed to contribute to neurotoxicity in prion diseases, including misfolded intermediates as well as cytosolic and transmembrane isoforms. To better understand PrP neurotoxicity, we analyzed the role of two highly conserved methionines in helix 3 on PrP biogenesis, folding and pathogenesis. Expression of the PrP-M205S and -M205,212S mutants in Drosophila led to hyperglycosylation, intracellular accumulation and widespread conformational changes due to failure of oxidative folding. Surprisingly, PrP-M205S and -M205,212S acquired a transmembrane topology (Ctm) previously linked to mutations in the signal peptide (SP) and the transmembrane domain (TMD). PrP-M205,212S also disrupted the accumulation of key neurodevelopmental proteins in lipid rafts, resulting in shortened axonal projections. These results uncover a new role for the hydrophobic domain in promoting oxidative folding and preventing the formation of neurotoxic Ctm PrP, mechanisms that may be relevant in the pathogenesis of both inherited and sporadic prion diseases.