生物谷报道:近日,拜尔医学院(BCM)的研究人员发表在“生物科学图书馆”在线版上的一篇报道声称:存在于果蝇和小鼠体内的一种称为烟酞胺核昔酸腺昔酞基转移酶(NMNAT) 的蛋白质可防止神经细胞退化。本文的高级作者、BCM发育生物学主任和霍华德•休斯医学研究所研究人员Hugo Bellen博士认为,此研究工作得赐于以下争论:即是否可以研制可刺激产生另外的蛋白产物从而保护导致疾病的退化或损伤的神经细胞。本研究重要之处在于证明了NMNAT是机体神经元生存所必需的重要因素。本文的大部分工作是由第一作者、Bellen实验室的博士后――来自中国的R. Grace Zhai完成。
五年前,科学家发现小鼠含有一个基因的三个拷贝,其中含有NMNAT和另一种蛋白质。Bellen和同事在果蝇和黑腹果蝇(一种常用的模式动物)体内研究NMNAT的突变体来观察NMNAT的神经保护作用。NMNAT单体只存在于果蝇,而且只有一种形式。
当Zhai、Bellen和同事们发现神经系统缺失蛋白的果蝇的神经元退化迅速,但是将他们放在暗处可降低退化过程并避免激活视神经元。若缺乏NMNAT蛋白,眼中的感光器发育正常,他们会伸出轴突(将神经卷曲延伸生长进入脑组织)和形成突触(具有连接神经轴突和靶细胞的功能)。但是在眼发育后期,昆虫在蛹期就可以感光。一旦神经元被激活,他们就会快速退化。在出生后两周就几乎没有神经元幸存。当果蝇在暗处饲养,相对于他们曝光于亮处神经元死亡还是很缓慢的。所以光激活显然是细胞大量变性的原因。当这些果蝇眼中有大量的NMNAT产生,然后在阳光下放置30天。他们发现只有20%的神经元死亡,这说明此蛋白对维持神经元的生存所必需的所在,此蛋白大量存在下可延缓神经退化过程。他们还发现不需要小鼠和脊椎动物的其他酶的帮助、只在NMNAT单独存在下就足以保护神经元。
Figure 1.Mutations in Complementation Group 3R4 Disrupt Synaptic Structures in Photoreceptor Terminals
(A–F) External morphology of the homozygous eyes of 3R41 (C) and 3R42 (E) are normal when compared to those of isogenized control (A). Red eye color marks heterozygous patches. (B), (D), and (F) ERG recordings of control and mutant eyes. Note the reduced depolarization and on/off response. Bar above trace in (B) indicates duration of light stimulus.
(G–I) TEM micrographs of lamina cartridges containing control, 3R41, and 3R42 mutant terminals, respectively. Demarcating glia are colored blue and photoreceptor terminals green to accentuate the structures. Note the photoreceptor terminals are disorganized in mutants. The yellow boxes in (G) and (I) indicate the regions shown in (J) and (K), respectively. The red boxes in (G) and (H) indicate the regions shown in (L) and (M), respectively. Scale bar in (G) for (G–I) indicates 1 μm.
(J) and (K) Individual terminals that are boxed in (G) and (I) (yellow boxes). nmnat mutant terminals have amorphic active zone structures (red arrows), aberrant capitate projections (blue arrows), aberrant mitochondria (yellow arrowheads), and abnormal membranes (yellow arrow), as well as an aberrant cytoskeleton (blue arrowheads), which are not observed in wild-type terminals. Scale bar indicates 200 nm.
(L) and (M) Individual active zones that are boxed in (G) and (H) (red boxes). Compared to the clearly defined wild-type active zone structure (L), nmnat mutant active zones are amorphic and reduced in size. Both wild-type and mutant T-bars are surrounded by synaptic vesicles. Scale bar indicates 200 nm.
(N) and (O) Quantification of synapse number and size. No significant difference was found in the average number of active zones per terminal between control (118 terminals counted), and 3R41 (93 terminals counted) or 3R42 (71 terminals counted). Synapse size was measured by the width of T-bar platform profile (L) (insert). The size of T-bars in either 3R41 (23 measured) or 3R42 (31 measured) is significantly reduced compared to the control (38 measured). An asterisk (*) indicates p < 0.05.
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PLoS Biol. 2006 Nov 28;4(12):e416
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相关基因 Pubmed Gene
Nmnat
Nicotinamide mononucleotide adenylytran