Distal axonal degeneration is a hallmark of many neuropathies. Traditionally we tended to think in a simpel degeneration-regeneration model. The celbody of each neuron, based on the functions of its residing nucleus, is key in regeneration, and all regeneration processes are anterograde. Failure of metabolic support for the cellbody causes an impairement in the function of the axon, due to the fact that the axon itself is poorly inhabited by ribosomes and mitochondia and thus the axon is totally dependent on support from its master, the cellbody. In 1997 Spencer at all described the degeneration proces using an analogy of the farthest meaddow, which is the first to be drowned from water support, if the waterpump fails. These analogies and metaphors always play a big role in our understanding and our apporach of scientific problems and clinical problems.     

The idea that axonal degeneration follows the metaphor of the last meaddow (letzte Wiese) is not in line with recent findings. Actually it is nearly a mirror image of what probably happens in reality.^[1]

It is not the cellbody, which is the victim of the metabolic assault, it is the axon itself, with it 1000 times greater volume of cytoplasm. The specific target in the axon is the retrograde transport of growthfactors, from the peripheral axon towards the cell body. This retrograde transport most probably forms the essence of survival of the neuron, and is the base of the  anterograde transportfunctions of the neuron. ^[2]

In the follwing picture, taken from David D Ginty et al this principle is nicely depicted:

Trk receptors on distal axons can become activated if binding to neurotrophin. This ligand–receptor complex will than be internalizes through endocytosis. Some of the vesicles are transported retrogradely to the cell body via microtubule-dependent transport mechanisms. The vesicle-associated Trk receptor arriving at the cell body will switch on growth signals such as PI3K and Erk5. The peripheral part of the neuron steers the central part. It is exactly as with the long believed central dogma of Watson and Crick: everything springs from the DNA...

So the message is that a variety of peripherally synthesized neurotrophins, such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 and 4 (NT3 and NT4) and their corresponding receptors, TrkA, B and C, expressed by neurons are key players in a subtle feedback system, and form the base of the ability of neurons to regenerate.

All these target-derived growth factors, binding to cell surface receptors on axons, sometimes more than one meter from the neuronal soma, play crucial roles in neuron-maintenance. The long-range retrograde signaling from these distal axons to neuronal cell bodies is another important factor to take into consideration. The Trk receptors are the primary retrograde signal carriers at the beginning of the vital feedback loop of each neuron. The neurotrophins thus play a key role in neuron survival, and supprort in a vital way many improtant biolgical processes, such as dendritic and axonal outgrowth, synapse formation, function and plasticity, cell migration, and differentiation.

Retrograde signaling thus is needed for neuron survival, and recent research has highlighted abnormalities in this intracellular trafficking process in a variety of neurodegenerative disorders, such as Alzheimer's disease and Charcot's disease, amyotrophic lateral sclerosis. 

Jan M. Keppel Hesselink, MD, PhD, september 2010 

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