Dataset Information

Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.

ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the human BDNF variant in both alleles (BDNF(Met/Met)). Compared with wild-type mice, BDNF(Met/Met) mice exhibited reduced CNS BDNF levels without a discernable effect on infarct size. Diminished BDNF levels in BDNF(Met/Met) mice were associated with greater deficits in post-stroke locomotor functions. Additionally, the BDNF(Met/Met) mice showed reduced angiogenesis and elevated expression of thrombospondin-1 (TSP-1) and its receptor CD36, anti-angiogenic factors. To assess the functional role of CD36 in antagonizing angiogenic response in Met homozygosity at the BDNF locus, we crossed BDNF(Met/Met) mice with CD36 knock-out mice. The double-mutant mice rescued the angiogenic deficit associated with the BDNF(Met/Met) mice without alterations in BDNF levels, indicating that the behavioral deficit in BDNF(Met/Met) mice after stroke is partly related to an unfavorable balance in pro-angiogenic BDNF and anti-angiogenic TSP-1/CD36. The results suggest that CD36 inhibition may be a viable strategy to enhance angiogenesis and possible recovery in human stroke victims who are Met homozygotes at codon 66 of the BDNF locus.

SUBMITTER: Qin L

PROVIDER: S-EPMC3308129 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.

Qin Luye L Kim Eunhee E Ratan Rajiv R Lee Francis S FS Cho Sunghee S

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110101 2

Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the huma ...[more]

PMID: 21228186

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Project description:The val(66)met polymorphism in brain-derived neurotrophic factor (BDNF) has been associated with poorer outcomes after stroke. The mechanism for this finding remains uncertain but might be related to the reduced motor system activation associated with this polymorphism in healthy people.The current study examined whether the presence of the BDNF val(66)met polymorphism is associated with reduced motor system activation after stroke.Forty-two patients with stroke who were enrolled in 1 of 2 studies of robot-assisted arm motor therapy participated in the study. All participants were tested for the BDNF val(66)met polymorphism followed by functional magnetic resonance imaging during affected hand movement.Participants averaged 12 months poststroke and had wide-ranging motor deficits (Fugl-Meyer scale scores=14-60). Brain activation in participants without the BDNF val(66)met polymorphism (n=26) spanned bilateral motor networks with a larger volume (total=334 cc) than that found in participants with this polymorphism (n=16) (97 cc). Regional analyses were consistent. Participants without this polymorphism showed larger ipsilesional primary sensorimotor cortex activation volume and magnitude compared with those in whom the polymorphism was present.The extent to which these findings generalize to other populations of people with stroke, such as those with stroke <7 days prior, remains uncertain.Functional magnetic resonance imaging during affected hand movement showed decreased brain activation among participants with the BDNF val(66)met polymorphism compared with those lacking this polymorphism, especially in the ipsilesional primary sensorimotor cortex contralateral to movement. These results echo findings in healthy people and suggest that genetic factors affecting the normal brain continue to be operative after stroke. The findings suggest a potential imaging-based endophenotype for the BDNF val(66)met polymorphism's effect on the motor system that may be useful in a clinical trial setting.

Project description:Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism.

Dataset Information

Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.

Publications

Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.

Similar Datasets

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