Identification of the BDNF prodomain (pBDNF) as a new pathogenic ligand affecting neuronal structure and function

MILENA JANDAR; FRANCIS S LEE; AGUSTIN ANASTASIA; HENRIETTA BAINS; BARBARA L HEMPSTEAD; JOANNA GIZA; CLAY BRACKEN

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

Federation of Latin American and Caribbean Neuroscience Societies (FALAN)

Brain-derived Neurotrophic Factor (BDNF) 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 single nucleotide polymorphism (SNP) in the BDNF gene that 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 increased risk for psychiatric and neurodegenerative disorders. We found, for the first time, that the Met pBDNF is an abundant active secreted ligand on CNS neurons inducing structural alterations and circuitry remodeling. Here, we demonstrate that the Met and Val pBDNF undergo interaction with zinc at physiologically relevant concentrations. These interactions result in differential aggregate formation between the Met and the Val prodomains, as assessed by cryo-electron microscopy. We have mapped the regions of the Met and Val prodomain that interact with zinc to promote aggregation utilizing point mutagenesis. Most importantly, these aggregation-deficient mutants of the Met prodomain demonstrate a loss of bioactivity, as determined by dendritic spine remodeling. This result documents that zinc-dependent aggregation of the Met pBDNF is required for bioactivity. We identify a mechanism by which the Met pBDNF mediates its biological effects, and propose targets for blocking the deleterious synapse remodeling effects in the human SNP carriers.