Impairments in axonal transport identified in multiple sclerosis

 

The complex and elaborate morphology of many types of neurons presents a problem for these cells: how can neurons deliver the appropriate molecules to the appropriate places, sometimes to regions many inches away from the site of production located in the cell body? To overcome this process, cells have developed an intricate transport system that allows new proteins and new messages and old proteins and old messages to travel in anterograde and retrograde directions to be appropriately incorporated or degraded at the proper final destination. This system, therefore, allows cells to get rid of old waste or misfolded/damaged proteins from distant functional sites while allowing new and needed proteins to be shipped back out to the areas of the cell that need them most at any given time. In the most recent issue of Neuron, Sorbara et al. identifies a disruption in this transport system in a model of progressive multiple sclerosis (MS), a disruption that the authors state could contribute to the axon dystrophy associated with the disease.

Multiple sclerosis is a disorder characterized by motor and sensory impairments, including issues of balance/coordination, episodes of blurred vision, and often times tingling and/or numbness. The specific symptoms depend on where in the nervous system the plaques, the hallmark lesion of MS, are located. MS is also characterized by “attacks” of symptoms, periods when symptoms are present, and then periods of remission. However, in many patients, the disorder eventually becomes secondary progressive, where the periods of remission are much shorter or much less frequent. Additionally, the primary progressive form is characterized by an absence of remission following the first sets of attacks. The classic pathophysiology included disruptions in axon myelination and decreases signal propagation. Though disruptions in axonal transport have been linked to many neurodegenerative diseases, evidence for this is still not well established for MS or other neuroinflammatory disorders.

To study whether transport is disrupted in MS, the authors used a mouse model of MS in which the spinal cords of these animals have inflammatory lesions and axonal degeneration. The authors then tracked the transport of individual cellular organelles by labeling these structures with a fluorescent tag that allowed for visual identification. These experiments showed that both the anterograde and retrograde types of transport described earlier were both significantly reduced in axons from the MS mice. Interestingly, this disrupted transport was present in both damaged/swollen axons and the more normal appearing neurons, suggesting that this process is widespread in MS-associated lesions.

In the next part of the study, the authors wanted to determine whether or not changes in the organelles themselves, such as organelle damage, contributed to the accumulation of organelles/disrupted transport. Analysis of the transport of both normal vs damaged mitochondria showed that transport was disrupted independent of damage. This data in combination with the fact that both normal looking and damaged axons show disrupted transport suggests that the deficits in organelle transport in axons precedes the actual axon or organelle damage. Additionally, the authors wanted to study whether or not change to the microtubules, the proteins that act as the railway tracks of the transport system, might be interfering with the normal organelle transport. Again, the defects in transport preceded any impairments or alterations of the microtubule system as measured by changes in microtubule modifications or orientations.

To conclude the study, the authors aimed at reversing the impairment in axonal transport. To do this, they turned to both anti-inflammatory and anti-oxidative treatments, as the deficits in transport seem to be more related to these processes rather than disruptions in organelles, microtubules, or axons themselves. In these experiments, both types of treatments were able to restart transport, suggesting that further developments of these specific treatments may be beneficial to MS patients. This type of therapy is still far off, but the evidence that disruptions in transport precede any structural damage could mean that the problem is preventable (as structural damage may be past the point of no return). A more complete study of the affects of these treatments on myelination and symptom recovery will be needed in these mice.

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