The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.
复制标题
DOI：
10.1016/j.brainres.2012.01.016
复制
发表时间：
2012-06-26
期刊：
影响因子：
2.9
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
King OD;Gitler AD;Shorter J
prion是在个体之间自然传播的蛋白质，并促进酵母中的表型变化领域排除了途径将此域附加到报告蛋白上可以赋予prion域。 9有一个假定的王室领域，其中12位是整个基因组中的60个主要候选者。疾病和亨廷顿疾病，例如FUS和TDP-43在候选RRM的prion王中，在ALS患者的退化运动神经元中形成了细胞质内含物，而TDP-43和FUS中的突变引起了农场ALS，最近引起了RNA结合的蛋白质抑制作用。到达冰山一角。通过我们的算法鉴定的RNA结合prion候选者将很快表现为潜水神经变性条件的遗传修饰剂或原因。
Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease and Huntington’s disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion-like domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system.
登录
查看更多内容
影响因子：
7.8
作者：
Buchan, J. Ross;Muhlrad, Denise;Parker, Roy
通讯作者：
Parker, Roy
影响因子：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
3.5
作者：
Ash, Peter E. A.;Zhang, Yong-Jie;Link, Christopher D.
通讯作者：
Link, Christopher D.
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.
DOI：
10.1073/pnas.082097899
发表时间：
2002-04-16
影响因子：
11.1
作者：
Baxa, U;Speransky, V;Wickner, RB
通讯作者：
Wickner, RB