Axonal transport is the process that is responsible for moving nutrients, proteins and other vital cellular cargo to and from the cell bodies in motor neurons – the muscle-controlling nerve cells that are lost in amyotrophic lateral sclerosis (ALS).
Abnormalities in axonal transport have been associated with ALS in previous studies. Now, findings from two new studies, one supported in part by MDA, shed light on what causes the process to malfunction — at least in SOD1-related ALS — and how it might be fixed.
Axonal transport takes place in axons (the long fibers that carry signals to and from other nerve cells or muscle cells) and its proper function is critical to motor neuron survival.
Cellular material is transported in two directions within the axons: away from the cell body (anterograde) and toward the cell body (retrograde). The process also has two speeds – slow and fast – which are determined by the type of material that is being transported.
A slowdown in in the axonal transport system may cause the distal end of the axon to run out of materials it needs in order to function properly – an event that could play a role in the death of the cell. (In ALS, motor neuron degeneration typically begins at the outer end of the axon and moves inward toward the nerve cell body. When connections to other nerve cells or muscles are lost, the nerve cell dies.)
A recent study has identified mutant SOD1 protein as the cause of a slowdown in one type of axonal transport — and results from a related study show that a “molecular chaperone” may be a possible solution to the problem.
In studies conducted in squid axons, mutated SOD1 protein inhibited anterograde (away from the cell body) fast axonal transport, while normal SOD1 protein did not, reports an MDA-supported research team based in the United States and Argentina. (Mutations in the gene for SOD1 are a known cause of ALS.)
Scott Brady at the University of Illinois at Chicago, and colleagues, found that mutated SOD1 protein boosted activity of the P38 mitogen-activated protein kinase (P38 MAPK) signaling pathway. In turn, the P38 MAPK protein modified the molecular “motors” that drive the transport process, leaving them unable to perform their job properly.
The findings suggest targeting SOD1 or its interactions with P38 MAPK protein potentially may be a therapeutic strategy in SOD1-related ALS.
MDA supported Brady and Lawrence J. Hayward, at the University of Massachusetts Medical Center in Worcester, for their work on this project.
The team published these findings online June 12, 2013, in PLoS One. To read the full report, at no cost, see: Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of P38 Map Kinase.
Researchers involved in a different study for related work (also was led by Brady) reported that slowdown in anterograde fast axonal transport caused by mutant SOD1 protein can be corrected with a “molecular chaperone” – a protein that assists in the proper folding and unfolding of other proteins.
In studies conducted in squid axons, the researchers found that adding heat shock protein 110 (HSP110) blocks SOD1 activation of P38 MAPK protein and completely corrects the transport defect.
They also found that even in the presence of mutant SOD1 protein, compounds that inhibit P38 MAPK normalized the rate of axonal transport.
The findings suggest the potential for ALS therapies based on targeting mutant SOD1 or its interactions with P38 MAPK protein, or targeting P38 MAPK itself.
The team published these findings online March 18, 2013, in Proceedings of the National Academy of Sciences. To read the full report, at no cost, see: Molecular Chaperone HSP110 Rescues a Vesicle Transport Defect Produced by an ALS-Associated Mutant SOD1 Protein in Squid Axoplasm.