Laboratory of Neurochemistry, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
J Alzheimers Dis. 2010;19(2):389-403. doi: 10.3233/JAD-2010-1243.
Pin1 [Protein Interacting with NIMA (never in mitosis A)] is a peptidyl prolyl cis-trans isomerase that isomerizes phospho-Serine/Threonine-Proline [p(S/T)-P] motifs of its target proteins. Pin1 functions in concert with proline directed kinases such as cyclin-dependent protein kinases, extracellular signal-regulated kinases, and c-Jun N- terminal kinase, and protein phosphatases such as protein phosphatase 2A (PP2A) and PP2B, in the regulation of a wide range of cellular processes including cell division, DNA damage response, and gene transcription, and in susceptibility to cancer and neurodegenerative diseases. This review focuses on the roles of Pin1 in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Frontotemporal dementia associated with parkinsonism linked to chromosome 17. Pin1 interacts with neuronal cytoskeletal proteins such as tau, amyloid-beta protein precursor, alpha-synuclein, and neurofilaments, often in association with phosphorylation events that influence their functions in the neuronal cytoskeleton. Overexpression of Pin1 reduces WT tau stability but increases P301L mutant tau stability. Pin1 associates with neurofilament H (NF-H) and modulates excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-H. Pin1 mediates the neural specific apoptosis machinery. The specific inhibitors of Pin1 may have potential therapeutic implications in neurodegeneration.
Pin1（与 NIMA 相互作用的蛋白）是一种肽基脯氨酰顺反异构酶，可使靶蛋白的磷酸丝氨酸/苏氨酸-脯氨酸 [p(S/T)-P] 基序发生异构化。Pin1 与周期蛋白依赖性蛋白激酶、细胞外信号调节激酶和 c-Jun N-末端激酶等脯氨酸定向激酶以及蛋白磷酸酶 2A（PP2A）和 PP2B 等蛋白磷酸酶协同作用，调节包括细胞分裂、DNA 损伤反应和基因转录在内的广泛的细胞过程，并易患癌症和神经退行性疾病。本综述重点介绍了 Pin1 在神经退行性疾病中的作用，包括阿尔茨海默病、帕金森病、肌萎缩侧索硬化症和额颞叶痴呆伴帕金森病相关的 17 号染色体相关。Pin1 与神经元细胞骨架蛋白相互作用，如 tau、淀粉样β蛋白前体、α-突触核蛋白和神经丝，通常与影响其在神经元细胞骨架中功能的磷酸化事件有关。Pin1 的过表达降低了 WT tau 的稳定性，但增加了 P301L 突变型 tau 的稳定性。Pin1 与神经丝 H（NF-H）结合，并调节兴奋毒性和氧化应激诱导的 NF-H 核周磷酸化。Pin1 介导神经特异性细胞凋亡机制。Pin1 的特异性抑制剂可能在神经退行性变中具有潜在的治疗意义。
