2012年12月6日讯 /生物谷BIOON/ --一项研究在细胞水平上了解了神经退行性疾病如帕金森氏症,阿尔茨海默氏症和亨廷顿氏病的发生发展过程,对打击这类疾病带来了一个新的认识。
神经退行性疾病导致运动功能或认知功能或两者降低,这是由大脑的特定区域负责这些功能退化导致的。
虽然这些功能与神经退行性疾病毒蛋白聚合有关,但有很多是机制如在细胞水平上哪种聚合引起神经毒性和死亡是未知的。由致病蛋白质聚集的结构包涵体长期被视为一个疾病的标志性物质,但包涵体和疾病之间的关系一直有些神秘。
在一项发表在PNAS杂志上研究中,这些历来被认为伴随着疾病发生的包涵体,实际上有一个与疾病没有必然联系的细胞生物功能。
此外,研究人员认为这些包涵体不仅是没有毒性的,实际上还发挥一种天然保护机制。研究人员已经确定了两个包涵体 JUNQ和IPOD。在JUNQ中蛋白聚集可能会导致毒性,而聚集在IPOD中则会发挥保护作用。
希伯来大学研究人员说,这些研究结果指出了一个新的潜在的战略治疗神经退行性疾病。取代非常困难的防止蛋白聚合的方法,封闭包涵体有害蛋白聚集的能力,从而中和进一步导致神经退行性损伤的有毒蛋白质。(生物谷:Bioon.com)
doi:10.1073/pnas.1205829109
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Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.
S. J. Weisberg, R. Lyakhovetsky, A.-c. Werdiger, A. D. Gitler, Y. Soen, D. Kaganovich.
Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.