Might impaired transport of material along axons be a critical factor in neurodegeneration?
The great length of many neurons poses a considerable challenge to communication between the cell body and nerve terminals. Intracellular transport systems are thus critical to neuron biology. And, as Dr Gipi Schiavo and colleagues have discovered, abnormalities in such systems can spell the end of the cell.
Dr Schiavo has had a long-standing interest in both pathogens and neuronal transport. In fact the two are connected, as several pathogens and pathogen products have hijacked the uptake and transport systems of neurons to enter cells and gain a free ride to the cell body. One such protein is tetanus toxin, and by adapting this protein Dr Schiavo has been able to develop probes to explore the mechanisms of neuronal transport.
Using mass spectrometry, he was able to show that transport from the nerve terminal to the cell body - axonal retrograde transport - is dependent on a surprisingly complex organelle containing many hundreds of proteins. At its heart is a molecular motor protein, dynein.
In 2003, work with Professor Elizabeth Fisher identified mutations in dynein in the 'Legs at odd angles' (Loa) mouse mutant, which shows late-onset neuromuscular degeneration. The mutant form of dynein was less able to support rapid retrograde transport in motor neurons. Since other genetic causes of neurodegeneration also affect retrograde transport, the results suggested that abnormal axonal transport could be important in a range of pathological conditions affecting the nervous system.
Indeed, work with Professor Linda Greensmith on another form of motor neuron disease, amyotrophic lateral sclerosis (ALS), provided further support for this idea. Using a newly developed assay, Dr Schiavo was able to visualise vesicle transport in living mice engineered to express a human ALS-causing gene. Significantly, defects in axonal retrograde transport were seen long before physical symptoms were apparent - implying that disruption of transport was an early and perhaps causal event in disease.
In 2013, Dr Schiavo moved from the CRUK London Research Institute to UCL, to forge closer links with Professor Fisher and Professor Greensmith, as well as with UCL's human geneticists and clinicians. Notably, components of neuronal transport systems identified in cellular studies have turned out to be involved in clinical conditions, and further analysis may reveal candidate causes of other unexplained cases. Furthermore, transport abnormalities have also been seen in other neurodegenerative conditions, including Alzheimer's and Huntington's disease, so the process may be of even wider significance.