PROBDNF BIOLOGY AND EMERGING ROLES IN THE CNS: THE UNEXPECTED JOURNEY OF PRONEUROTROPHINS

Neurotrophins are synthetized as precursors (proneurotrophins) with a N-terminal prodomain and a C-terminal mature domain. Classically, neurotrophins must be cleaved off their prodomains to be operational. That is to promote neuronal and non-neuronal cell survival, growth and differentiation via rapid signaling routes and long lasting changes in gene transcription. This view came with the assumption that the proforms of all neurotrophins are inactive. But since the early 2000s, several laboratories driven by the group of Dr. Barbara L. Hempstead revealed that the proforms are signaling molecules as well. Proneurotrophins can be secreted and bind specifically and with high affinity to the p75 neurotrophin receptor (p75 NTR) as receptor. Recent studies on Brain Derived Neurotrophic Factor (BDNF) demonstrated that proBDNF effects via p75 NTR opposes the functions of mature BDNF through its cognate tropomyosin related kinase B (TrkB) receptor. These antagonistic effects include synaptic plasticity (depression versus potentiation), dendritic spine maintenance (elimination versus growth) and cell fate (death versus survival). In this chapter we will review proBDNF intracellular and extracellular processing, transport, signaling mechanisms, as well as its biological function in health and disease. We will focus on the effect of a common human polymorphism in the BDNF gene inducing a Val66Met substitution that causes structural remodeling of the prodomain promoting a gain of function of this peptide independently of mature BDNF. Given their features, neurotrophins have been implicated in numerous neurodegenerative diseases and psychiatric disorders in which the Met66 allele human carriers are more vulnerable than the Val66 carriers.