Neurotrophic Factors

A new report in the Proceedings of the National Academy of Sciences (PNAS) provides insights into the mechanisms underlying the targeting of brain-derived neurotrophic factor (BDNF) transcripts to distinct cellular compartments in neurons. While previous evidence had suggested that targeting of dendrites by BDNF mRNA transcripts plays a key role in mediating synaptic plasticity the molecular mechanisms remain unknown.  Chiaruttini et al provide evidence that the translin/trax complex mediates dendritic targeting of BDNF mRNA and this targeting is disrupted by the G196A (Val66Met) mutation that has been implicated in cognitive and psychiatric impairments, especially memory deficits and depression. This suggests that there is a link between defects in dendritic trafficking and susceptibility to cognitive and mood disorders, although Chiaruttini et al caution that impaired binding of BDNF to the sorting protein, sortilin, may also be involved.

An association between the BDNF Val66Met polymorphism and susceptibility to cognitive and mood disorders in different neurological and psychiatric disorders including Parkinson’s disease (PD) has been suggested previously but findings have been mixed. Two recent reports explored a role of the polymorphism in both cognitive and motor impairments in PD. Guerini et al (2009) studied an Italian cohort of 294 PD patients that included patients with impaired (n = 29) or normal cognition (n = 265) and 233 age-matched control subjects. They found a difference in the distribution of the BDNF polymorphism in the entire PD group compared to the control subjects but this difference was lost when the cognitively impaired PD patients were excluded. The BDNF polymorphism was more common in the group of cognitively impaired PD patients compared to the other two groups suggesting that it is not a risk factor for the occurrence of PD but rather a reflection of cognitive impairment in some of the PD patients.  

In another recent study, Foltynie et al (2009) examined the possibility that the BDNF Val66Met polymorphism influences the development of levodopa induced dyskinesia (LID) in PD through its effects on activity dependant modulation of synaptic plasticity. They evaluated the influence of the polymorphism on the risk of developing dyskinesias in 315 PD patients and found a significant difference in the time to onset of LID according to BDNF Val66Met genotype, with val/val homozygotes having the longest time to onset, heterozygotes midway, and met/met homozygotes developing LID earliest. While these results need to be replicated and the pathophysiological mechanisms elucidated they could potentially influence treatment decisions in PD patients with met alleles.

C. Chiaruttini, A. Vicario, Z. Li, G. Baj, P. Braiuca, Y. Wu, F. S. Lee, L. Gardossi, J. M. Baraban and E. Tongiorgi. Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. PNAS Published online September 9, 2009, doi: 10.1073/pnas.0902833106