The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration.
The Unfolded Protein Response and the Role of Protein Disulfide Isomerase in Neurodegeneration.
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DOI：
10.3389/fcell.2015.00080
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发表时间：
2015
影响因子：
5.5
通讯作者：
Atkin JD
中科院分区：
文献类型：
--
作者：
Perri ER;Thomas CJ;Parakh S;Spencer DM;Atkin JD
蛋白质稳态的维持和调节是有丝分裂后神经元的关键功能，其失调与神经退行性疾病越来越相关。尽管有不同的临床表现，但这些疾病具有相似的病理学；神经元中错误折叠蛋白质的积累以及随后细胞蛋白质稳态的破坏。内质网（ER）是蛋白质稳态的重要组成部分，当内质网内发生错误折叠蛋白质的积累时，会扰乱内质网稳态，引起内质网应激。这会触发未折叠蛋白反应 (UPR)，这是一种独特的信号传导途径，虽然最初具有保护性，但如果 ER 应激延长，则会促进细胞凋亡。 ER 应激越来越多地与神经退行性疾病相关，新出现的证据强调了 UPR 在这些疾病中的复杂性，同时描述了保护性和有害性成分。蛋白质二硫键异构酶 (PDI) 是内质网应激期间诱导的内质网伴侣，负责蛋白质中二硫键的形成。虽然最初被认为具有保护作用，但最近的研究揭示了 PDI 在神经退行性疾病中的非常规作用，与其在 UPR 和 ER 中的正常功能不同，尽管这些机制仍不清楚。然而，PDI 功能的特定方面可能提供未来在治疗上开发的潜力。本综述将重点关注将 ER 应激和 UPR 与神经退行性疾病联系起来的证据，特别强调 PDI 在这些情况下出现的新功能。
The maintenance and regulation of proteostasis is a critical function for post-mitotic neurons and its dysregulation is increasingly implicated in neurodegenerative diseases. Despite having different clinical manifestations, these disorders share similar pathology; an accumulation of misfolded proteins in neurons and subsequent disruption to cellular proteostasis. The endoplasmic reticulum (ER) is an important component of proteostasis, and when the accumulation of misfolded proteins occurs within the ER, this disturbs ER homeostasis, giving rise to ER stress. This triggers the unfolded protein response (UPR), distinct signaling pathways that whilst initially protective, are pro-apoptotic if ER stress is prolonged. ER stress is increasingly implicated in neurodegenerative diseases, and emerging evidence highlights the complexity of the UPR in these disorders, with both protective and detrimental components being described. Protein Disulfide Isomerase (PDI) is an ER chaperone induced during ER stress that is responsible for the formation of disulfide bonds in proteins. Whilst initially considered to be protective, recent studies have revealed unconventional roles for PDI in neurodegenerative diseases, distinct from its normal function in the UPR and the ER, although these mechanisms remain poorly defined. However, specific aspects of PDI function may offer the potential to be exploited therapeutically in the future. This review will focus on the evidence linking ER stress and the UPR to neurodegenerative diseases, with particular emphasis on the emerging functions ascribed to PDI in these conditions.