Schneider Benoit, Baudry Anne, Pietri Mathéa, Alleaume-Butaux Aurélie, Bizingre Chloé, Nioche Pierre, Kellermann Odile, Launay Jean-Marie
Inserm UMR-S1124, Paris, France.
Université de Paris, Faculté des Sciences, Paris, France.
Front Cell Neurosci. 2021 Apr 12;15:660683. doi: 10.3389/fncel.2021.660683. eCollection 2021.
Amyloid-based neurodegenerative diseases such as prion, Alzheimer's, and Parkinson's diseases have distinct etiologies and clinical manifestations, but they share common pathological events. These diseases are caused by abnormally folded proteins (pathogenic prions PrP in prion diseases, β-amyloids/Aβ and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease) that display β-sheet-enriched structures, propagate and accumulate in the nervous central system, and trigger neuronal death. In prion diseases, PrP-induced corruption of the physiological functions exerted by normal cellular prion proteins (PrP) present at the cell surface of neurons is at the root of neuronal death. For a decade, PrP emerges as a common cell surface receptor for other amyloids such as Aβ and α-synuclein, which relays, at least in part, their toxicity. In lipid-rafts of the plasma membrane, PrP exerts a signaling function and controls a set of effectors involved in neuronal homeostasis, among which are the RhoA-associated coiled-coil containing kinases (ROCKs). Here we review (i) how PrP controls ROCKs, (ii) how PrP-ROCK coupling contributes to neuronal homeostasis, and (iii) how the deregulation of the PrP-ROCK connection in amyloid-based neurodegenerative diseases triggers a loss of neuronal polarity, affects neurotransmitter-associated functions, contributes to the endoplasmic reticulum stress cascade, renders diseased neurons highly sensitive to neuroinflammation, and amplifies the production of neurotoxic amyloids.
基于淀粉样蛋白的神经退行性疾病，如朊病毒病、阿尔茨海默病和帕金森病，具有不同的病因和临床表现，但它们有共同的病理过程。这些疾病是由异常折叠的蛋白质（朊病毒病中的致病性朊病毒PrP、阿尔茨海默病中的β-淀粉样蛋白/Aβ和Tau、帕金森病中的α-突触核蛋白）引起的，这些蛋白质呈现富含β-折叠的结构，在中枢神经系统中传播和积累，并引发神经元死亡。在朊病毒病中，PrP导致神经元表面存在的正常细胞朊病毒蛋白（PrP）所发挥的生理功能受损，这是神经元死亡的根源。十年来，PrP已成为其他淀粉样蛋白（如Aβ和α-突触核蛋白）的共同细胞表面受体，这些淀粉样蛋白至少部分地传递其毒性。在质膜的脂筏中，PrP发挥信号功能并控制一组参与神经元稳态的效应器，其中包括RhoA相关的含卷曲螺旋结构域激酶（ROCKs）。在这里，我们综述：（i）PrP如何控制ROCKs；（ii）PrP-ROCK偶联如何促进神经元稳态；以及（iii）在基于淀粉样蛋白的神经退行性疾病中，PrP-ROCK连接的失调如何引发神经元极性丧失、影响神经递质相关功能、促成内质网应激级联反应、使患病神经元对神经炎症高度敏感，并放大神经毒性淀粉样蛋白的产生。
