Trafficking of neurotrophins and their receptors and pathological significance

Abstract

To survive and function properly, innervating neurons need to communicate with their targets. This task is accomplished, in part, by trafficking of neurotrophic molecules, in particular the family of nerve growth factor-like molecules, the neurotrophins (NTs). This chapter reviews the intra- and intercellular trafficking of NTs and their receptors with a focus on axonal transport and synaptic transfer, methodology, current concepts, and the relevance for pathological neurological conditions. Neurotrophins are transported by retrograde axonal transport from the neuronal or non-neuronal target cells to the innervating neuronal cell body. The neurotrophic hypothesis postulates that targets produce limiting amounts of trophic substances, including NTs, for which innervating neurons compete. NTs bind to NT receptors on axonal terminals and are internalized, presumably in vesicles or endosomes (signaling endosome hypothesis), and are transported by dynein-mediated retrograde axonal transport along microtubules to the cell body where the NT-specific receptors (trkA, B, and C) elicit signal transduction cascades that result in increased neuronal survival, differentiation, and/or plasticity. In addition to the retrograde route, NTs can also be transported anterogradely along axons and can be released at the axon terminal to influence postsynaptic cells. Thus, NTs can transfer in both directions across the synaptic cleft. NT receptors are expressed on the presynaptic as well as postsynaptic membrane, allowing for the activation of signal cascades at pre- as well as postsynaptic sites. NTs such as BDNF and NT-3 are particularly important messengers in synaptic plasticity. In addition to mature NTs, uncleaved precursors (pro-NTs) can also be trafficked and released, and their actions can oppose the functions of mature NTs by activating death signaling through the common NT receptor, p75. Several neurological disorders are currently being investigated for defects in NT trafficking, including Alzheimer's disease, Huntington's disease, Parkinson's disease, neurodevelopmental disorders, epilepsy, glaucoma, hyperalgesia, neuropathies, depression, and eating disorders. Progress in the understanding of physiological and pathological mechanisms of NT trafficking therefore may lead to improved therapies for neurological diseases.