Misfolded PrP and a novel mechanism of proteasome inhibition
Misfolded PrP and a novel mechanism of proteasome inhibition
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DOI：
10.4161/pri.6.1.18272
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发表时间：
2012-01-01
期刊：
影响因子：
2.3
通讯作者：
Tabrizi, Sarah J.
中科院分区：
文献类型：
--
作者：
Andre, Ralph;Tabrizi, Sarah J.
朊病毒疾病包括一个致命的神经退行性疾病家族，由正常宿主编码蛋白PrPC的构象重排到异常感染性异构体PrPSc引起。目前，朊病毒病发病机制的确切细胞机制尚不清楚。有证据表明泛素蛋白酶体系统（UPS）的作用，这是一种蛋白质降解途径，对维持细胞蛋白质稳态至关重要。UPS功能障碍与多种神经退行性疾病有关。然而，在许多情况下，这种损伤的机制仍然未知，并且缺乏与疾病相关的错误折叠蛋白能够直接抑制蛋白酶体功能的证据。最近，我们已经展示的数据描述了蛋白酶体损伤的机制，通过富含β -sheet- PrP的直接相互作用来减少门打开并抑制底物进入。这种新机制可能为其他错误折叠的疾病相关蛋白如何与蛋白酶体相互作用以破坏其功能提供了一个模型。在错误折叠蛋白积累的神经退行性疾病中，靶向UPS来恢复蛋白质平衡为治疗干预提供了一个可能的目标。
Prion diseases comprise a family of fatal neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded protein, PrPC, to an abnormal infectious isoform termed PrPSc. Currently, the precise cellular mechanism(s) underlying prion disease pathogenesis remain unclear. Evidence suggests a role for the ubiquitin proteasome system (UPS), a protein degradation pathway that is critical for maintaining cellular proteostasis. Dysfunction of the UPS has been implicated in various neurodegenerative diseases. However, the mechanisms of this impairment remain unknown in many cases, and evidence that disease-associated misfolded proteins are able to directly inhibit the function of the proteasome has been lacking. Recently, we have shown data describing a mechanism of proteasome impairment by the direct interaction of beta-sheet-rich PrP to reduce gate opening and inhibit substrate entry. This novel mechanism may provide a model for how other misfolded, disease-associated proteins might interact with the proteasome to disrupt its function. Targeting the UPS to restore proteostasis in neurodegenerative disorders in which misfolded proteins accumulate offers a possible target for therapeutic intervention.