Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation

doi:10.1073/pnas.0902833106

Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation

^aBRAIN Centre for Neuroscience, Department of Life Sciences, and
^cDipartimento di Scienze Farmaceutiche, University of Trieste, 34127 Trieste, Italy;
^bSolomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205; and
^dDepartment of Psychiatry, Cornell-Weill School of Medicine, New York, NY 10065

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 31, 2009
↵¹C.C. and A.V. contributed equally to this work.
↵²L.Z. and B.G contributed equally to this work. (received for review April 16, 2009)

Abstract

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.

Footnotes

³To whom correspondence should be addressed. E-mail: tongi{at}units.it
Author contributions: L.G., J.M.B., and E.T. designed research; C.C., A.V., Z.L., G.B., P.B., and Y.W. performed research; F.S.L. contributed new reagents/analytic tools; C.C., A.V., Z.L., G.B., P.B., L.G., J.M.B., and E.T. analyzed data; and A.V., J.M.B., and E.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0902833106/DCSupplemental.