Nandkishore R Belur, Bernabe I Bustos, Steven J Lubbe, Joseph R Mazzulli
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引用次数: 0
Abstract
Neurodegenerative diseases are commonly classified as proteinopathies that are defined by the aggregation of a specific protein. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are classified as synucleinopathies since α-synuclein (α-syn)-containing inclusions histopathologically define these diseases. Unbiased biochemical analysis of PD and DLB patient material unexpectedly revealed novel pathological inclusions in the nucleus comprising adenosine-to-inosine (A-to-I)-edited mRNAs and NONO and SFPQ proteins. These inclusions showed no colocalization with Lewy bodies and accumulated at levels comparable to α-syn. NONO and SFPQ aggregates reduced the expression of the editing inhibitor ADAR3, increasing A-to-I editing mainly within human-specific, Alu-repeat regions of axon, synaptic, and mitochondrial transcripts. Inosine-containing transcripts aberrantly accumulated in the nucleus, bound tighter to recombinant purified SFPQ in vitro, and potentiated SFPQ aggregation in human dopamine neurons, resulting in a self-propagating pathological state. Our data offer new insight into the inclusion composition and pathophysiology of PD and DLB.
神经退行性疾病通常被归类为蛋白质病,由特定蛋白质的聚集而定义。帕金森病(Parkinson's disease,PD)和路易体痴呆(Dementia with Lewy bodies,DLB)被归类为突触核蛋白病(synucleinopathies),因为从组织病理学角度看,含有α-突触核蛋白(α-syn)的包涵体是这些疾病的特征。对PD和DLB患者材料进行的无偏见生化分析意外地发现了细胞核中的新型病理包涵体,其中包括腺苷-肌苷(A-to-I)编辑的mRNA以及NONO和SFPQ蛋白。这些内含物未显示出与路易体的共定位,其累积水平与α-syn相当。NONO和SFPQ聚集体减少了编辑抑制剂ADAR3的表达,主要在轴突、突触和线粒体转录本的人类特异性Alu重复区域内增加了A-to-I编辑。含肌苷的转录本在细胞核中异常积累,在体外与重组纯化的SFPQ结合得更紧密,并在人类多巴胺神经元中增强了SFPQ的聚集,导致了一种自我传播的病理状态。我们的数据为了解帕金森病和多发性硬化症的包涵体组成和病理生理学提供了新的视角。
期刊介绍:
Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.