Impact of the Val66Met polymorphism on the BDNF gene on the structure and function of dopaminergic neurons.

CONSTANZA MILENA JANDAR PAZ; AGUSTÍN ANASTASÍA GONZALEZ

Cordoba

Congreso; SAN 2018; 2018

Sociedad Argentina de Investigación en Neurociencias

A single nucleotide polymorphism (SNP) in the BDNF gene is present in more than 25% of the human population, and it results in a valine (Val) for methionine (Met) substitution (Val66Met) within its prodomain sequence. This SNP is associated with increased susceptibility to develop certain psychiatric and neurodegenerative disorders. Some of the associated diseases involve dopaminergic (DA) neuron dysfunction such as schizophrenia, addictions and, in some populations, Parkinson?s disease. It has been demonstrated that the Met variant of the BDNF prodomain affects hippocampal neuron structure, but its effects on DA neurons remain to be studied. We hypothesized that the Met variant of the BDNF prodomain affects DA neuron structure and function. Interestingly, we found that stimulation with the Met prodomain (but not the Val variant) induces superior cervical ganglion DA neuron death in culture. Moreover, mesencephalic DA neurons cultured from BDNF Met/Met knock-in mice displayed shorter processes as compared to the Val/Val littermates. Finally, BDNF Met/Met mice show increased spontaneous ipsilateral turns after the unilateral injection of the specific DA neurotoxin 6-hydroxydopamine, suggesting that DA neurons from this genotype are more susceptible to degenerate compared to Val/Val mice. Altogether, these results suggest a molecular explanation for the increased incidence of DA-related central nervous system disorders in Val66Met carriers.