Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation
Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation
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DOI：
10.1073/pnas.0902833106
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发表时间：
2009-09-22
影响因子：
11.1
通讯作者：
Tongiorgi, E.
中科院分区：
文献类型：
--
作者：
Chiaruttini, C.;Vicario, A.;Tongiorgi, E.
选择性剪接的脑源性神经营养因子（BDNF）转录物靶向神经元中不同的细胞区室，但这种分类的机制尚不清楚。尽管只有一些 BDNF 同工型靶向树突，但我们发现所有 BDNF 转录本共有的编码区包含组成型活性树突靶向信号，并且该信号在包含外显子 1 或 4 的转录本中受到抑制，这些外显子仅限于细胞体和近端树突。这种树突靶向信号由易位蛋白（一种参与 RNA 运输的 RNA 结合蛋白）介导，并被与记忆缺陷和精神疾病相关的 G196A 突变破坏。分子模型和突变研究表明，G196A 突变通过破坏 BDNF mRNA 与易位蛋白的相互作用来阻断 BDNF mRNA 的树突靶向。这些发现表明 BDNF mRNA 的树突状运输异常与 G196A 突变相关的神经精神疾病的病理生理学有关。
Alternatively spliced brain-derived neurotrophic factor (BDNF) transcripts are targeted to distinct cellular compartments in neurons but the mechanisms underlying this sorting are unknown. Although only some BDNF isoforms are targeted to dendrites, we have found that the coding region common to all BDNF transcripts contains a constitutively active dendritic targeting signal and that this signal is suppressed in transcripts containing exons 1 or 4, which are restricted to the cell soma and proximal dendrites. This dendritic targeting signal is mediated by translin, an RNA-binding protein implicated in RNA trafficking, and is disrupted by the G196A mutation associated with memory deficits and psychiatric disorders. Molecular modeling and mutational studies indicate that the G196A mutation blocks dendritic targeting of BDNF mRNA by disrupting its interaction with translin. These findings implicate abnormal dendritic trafficking of BDNF mRNA in the pathophysiology of neuropsychiatric disorders linked to the G196A mutation.