Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y, Lee F S, Gardossi L, Baraban J M, Tongiorgi E
BRAIN Centre for Neuroscience, Department of Life Sciences, and Dipartimento di Scienze Farmaceutiche, University of Trieste, 34127 Trieste, Italy.
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16481-6. doi: 10.1073/pnas.0902833106. Epub 2009 Sep 9.
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.
可变剪接的脑源性神经营养因子（BDNF）转录本靶向神经元中的不同细胞区室，但这种分选的潜在机制尚不清楚。尽管只有一些BDNF异构体靶向树突，但我们发现所有BDNF转录本共有的编码区包含一个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的转录本中被抑制，外显子1或4局限于细胞体和近端树突。这种树突靶向信号由转位蛋白介导，转位蛋白是一种与RNA运输有关的RNA结合蛋白，并被与记忆缺陷和精神疾病相关的G196A突变破坏。分子建模和突变研究表明，G196A突变通过破坏BDNF mRNA与转位蛋白的相互作用来阻断其树突靶向。这些发现表明BDNF mRNA的异常树突运输与与G196A突变相关的神经精神疾病的病理生理学有关。
