Neurotrophins and neurodegenerative diseases: receptors stuck in traffic?

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.