King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London SE5 9RT, UK.
Jozef Stefan Institute, Department of Biotechnology, 1000 Ljubljana, Slovenia.
Brain. 2021 Nov 29;144(10):2915-2932. doi: 10.1093/brain/awab201.
Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.
神经退行性蛋白病的特征是进行性细胞丧失，在此之前，蛋白质发生定位错误和异常积累，易于聚集。尽管它们具有不同的生理功能，但与疾病相关的蛋白质，如 tau、α-突触核蛋白、TAR DNA 结合蛋白-43、肉瘤融合蛋白和突变型亨廷顿蛋白，都具有可以介导它们液-液相转变的低复杂度区域。蛋白质的相转变范围可以从天然单体到可溶性寡聚物、液滴，再到不可逆的、通常定位错误的聚集体，这些聚集体是神经退行性疾病的阶段和严重程度的特征。最近对潜在发病机制的研究将与疾病相关的蛋白质的定位错误和异常积累与核质转运及其介导蛋白核孔蛋白的缺陷联系起来。这些研究在肌萎缩侧索硬化症、额颞叶痴呆症、阿尔茨海默病和神经原纤维缠结病（包括帕金森病和路易体痴呆症）中发现了核孔蛋白异常，从改变的表达水平到核孔蛋白 α 和 β 蛋白的亚细胞定位错误和聚集。这些研究结果表明，核孔蛋白除了在核输入和输出中的经典功能外，还可以作为伴侣蛋白，通过屏蔽易于聚集的蛋白质，防止错误折叠、积累和不可逆的相转变为不溶性聚集体。因此，核孔蛋白异常既可以是蛋白质定位错误和聚集体形成的原因，也可以是结果，这是退行性蛋白病中核孔蛋白病和蛋白病的恶性循环。核孔蛋白异常作为神经退行性疾病发病和进展的共同因素，确定了核孔蛋白异常是神经退行性蛋白病治疗的一个有前途的新靶点。核孔蛋白的药理学靶向已经作为治疗癌症（如胶质母细胞瘤）和病毒感染（如 COVID-19）的治疗干预措施进入临床试验，因此可能代表神经退行性蛋白病治疗的一个有前途的新途径。
