The BDNF prodomain (pBDNF) induces neuronal morphological changes associated with neuropsychiatric and neurodegenerative diseases.

AGUSTÍN ANASTASÍA GONZALEZ

Mar del Plata

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2015

Sociedad Argentina de Investigación en Neurociencias

Brain-derived Neurotrophic Factor (BDNF), which is the most highly expressed and studied neurotrophic factor in the mammalian brain, is translated as a precursor protein (proBDNF) that is cleaved to two peptides known as the BDNF prodomain (pBDNF) and mature BDNF (mBDNF). There is a common human single nucleotide polymorphism (SNP) in the BDNF gene which leads to a valine for methionine substitution (Val66Met) within the pBDNF sequence. The Val66Met SNP is present in more than 25% of the human population, and is associated with cognitive deficits and increased risk for neuropsychiatric and neurodegenerative disorders. We have recently shown, for the first time, that the Met66 pBDNF is an abundant active secreted ligand in the hippocampus that induces neuronal growth cone retraction (Anastasia et al., 2013. Nature communications 4:2490), dendritic spine collapse and consequently circuitry remodeling in this brain area. Surprisingly, pBDNF is also very abundant in the cerebrospinal fluid of adult humans. Utilizing nuclear magnetic resonance and other biophysical approaches we found that the Val66Met substitution induces structural changes in pBDNF that are responsible for the functional differences. We conclude that the neuronal morphology remodeling induced by the Met66 pBDNF, which is mediated by a receptor complex of SorCS2 and p75NTR, is a mechanism that contributes to the altered neuronal plasticity in humans with the SNP. Therefore, our research offers a molecular explanation for the increased incidence of neuropsychiatric and neurodegenerative disorders in Met66 human carriers, and provides a new candidate target for therapeutic intervention.