Human BDNF Isoforms are Differentially Expressed in Cocaine Addicts and are Sorted to the Regulated Secretory Pathway Independent of the Met66 Substitution |
| |
Authors: | Xueying Jiang Jian Zhou Deborah C Mash Ann M Marini Robert H Lipsky |
| |
Institution: | (1) Section on Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 3S32, MSC 9412, Bethesda, MD 20892-9412, USA;(2) Department of Neurology, University of Miami Medical School, Miami, FL, USA;(3) Department of Neurology and Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, MD, USA |
| |
Abstract: | Differential BDNF gene (BDNF) promoter use leads to protein isoforms differing by 8 or 15 N-terminal residues (BDNF1 and BDNF2) whose regulation and function
are not completely understood versus the well-known 247-aa BDNF “short” form. To describe how BDNF isoform levels were regulated by chronic drug use, we measured BDNF isoform-specific mRNA levels in different human brain regions from cocaine addicts relative to age, race, and gender-matched
controls. The cocaine group had threefold higher levels of exon 4-specific (BDNF Short) mRNAs in cerebellum versus controls
(P < 0.01). In cortex, exon 4 and exon 1-specific BDNF mRNA levels (BDNF1) were significantly reduced in the cocaine group relative to controls (40%, P < 0.01). We also tested the hypothesis that the signal peptides of isoforms BDNF1 and BDNF2 confer different functional properties
and determined if the functional Val66Met polymorphism influenced these functions. In contrast to transfected AtT-20 cells
producing BDNF Short, regulated secretion of BDNF1 or BDNF2 was not affected by the Met66 substitution. Hippocampal neurons
producing BDNF1 or BDNF2 on either the Val66 or Met66 background were similarly distributed in dendrites and had similar colocalization
patterns with the secretory granule marker Sec II. This pattern differed from neurons producing BDNF Short Met66, which had
impaired trafficking. Together, these findings support a mechanism by which variant BDNF proteins can overcome the functional
defect of the Met66 substitution and suggest how functional differences in BDNF may impact brain responses in disease.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
| |
Keywords: | Brain-derived neurotrophic factor Signal peptide Isoform Polymorphism Trafficking Regulated secretion mRNA Cocaine |
本文献已被 PubMed SpringerLink 等数据库收录! |
|