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Neurotrophins are well known for their physiological role as key modulators of neuronal survival, neurite out-growth, and synaptic connectivity during development and into adulthood. Moreover, neurotrophins are potent agents, ameliorating neuronal degeneration in many model systems for neurological diseases. However, a causal role for mutations in neurotrophins or neurotrophin receptors in human neurodegenerative diseases has been largely lacking. As neurotrophin receptors are located at synapses and as their signaling involves the neuronal nucleus, they need to bridge tantalizing distances in order to retrogradely communicate their survival signals. On the other hand, anterogradely transported neurotrophins are released at the synapse and act on postsynaptic cells. Antero- and retrograde signaling and trafficking is an emerging focus of interest in neurotrophin research. Some neurodegenerative diseases are known to affect transport of organelles. Thus, it appears likely that neurodegeneration could be caused by "indirect" effects on neurotrophin trafficking and, hence, signaling. In this review we summarize recent work on neurotrophins in neurodegenerative diseases with special focus on possible implications of disturbed trafficking of organelles and retrograde axonal signaling.

During development, targets of outgrowing axons produce neurotrophins. These signaling molecules exert short-distance effects on neuronal growth cones as well as long-distance effects on neuronal cell bodies and nuclei. The retrograde signaling from axon tips to cell bodies is essential for the regulation of neuronal survival during the period of naturally occurring programmed cell death in the nervous system. During this time window, neurons that fail to establish appropriate connections with their target tissues are eliminated by apoptosis. Neurotrophins (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5) may influence neuronal survival not only via signaling through Trk receptors but also through interactions with p75NTR. Retrograde transport of neurotrophins and their receptors within organelles coined ‘signaling endosomes’ is one potential mechanism contributing to retrograde signaling. However, alternative pathways not involving retrograde transport of neurotrophins are emerging. The current models of retrograde neurotrophin signaling from synapses to cell bodies are discussed, with special focus on potential roles of the enigmatic p75NTR receptor in neurotrophin trafficking.

Neuronal survival is dependent on continuous trophic stimulation by neurotrophic factors. Anterograde and retrograde transport of neurotrophic factors and their receptors within neurites is essential for the communication of these survival signals. Lack of neurotrophic input has been proposed as a pathomechanism leading to neurodegenerative disease. The present short review provides a summary of some of the recent data on neurotrophic factors in neurodegenerative disorders and describes how disturbances of axonal trafficking might deprive neurons from trophic input.