A neuron transmits information via its process, the axon. The axon is wrapped by the myelin sheath, which is required for efficient nerve conduction. Although myelin destruction (demyelination) is a cardinal feature in multiple sclerosis (MS), axonal damage also occurs. Since the primary target in MS is myelin or myelin- forming cells, the oligodendrocytes, axonal injury is believed to occur secondarily after myelin and oligodendrocytes are damaged. In this Outside-In destruction model, lesions develop from the outside (myelin) to the inside (axon). However, in an animal model for MS, Theiler's murine encephalomyelitis virus (TMEV) infection, axonal damage precedes demyelination. In TMEV infection, the distribution of axonal damage during the early phase corresponds to regions where subsequent demyelination occurs during the chronic phase. This suggests that initial axonal damage may alter the local microenvironment, resulting in the recruitment of inflammatory cells to the site of axonal degeneration, which in turn leads to demyelination. In this scenario, lesions can develop from the inside (axon) to the outside (myelin) (Inside-Out model). While it is not known why distinct areas of the brain are involved in MS, preceding axonal damage might play an important role in targeting inflammatory cells to particular sites in the brain. First, we will determine whether experimentally induced axonal damage alters the distribution of inflammatory demyelinating lesions in a viral model for MS, TMEV infection, and an autoimmune model for MS, experimental autoimmune encephalomyelitis (EAE), by modulation of expression of adhesion molecules, cytokines and chemokines. Second, we will compare wild- type mice with genetically mutant mice (C57BL/WldS mice) that lack (or delay) axonal degeneration to investigate roles of axonal damage in TMEV infection and EAE. Interactions between axons and myelin/oligodendrocytes are important for oligodendrocyte and axon survival. Thus, axonal injury itself can induce oligodendrocyte death, leading to the spread of demyelination. Since the mutant mice lack axonal degeneration, the extent of demyelination will be smaller in mutant mice than in wild-type mice. On the other hand, axonal degeneration might play a beneficial role for hosts in virus infection. Some viruses, including TMEV, can spread in the brain using axons. In this case, axonal degeneration can inhibit axonal transport of viruses and suppress virus dissemination in the brain. Since axonal injury in MS contributes to permanent neurological deficits, protection from or treatment of such injury would ameliorate the devastating effects of MS. A spectrum of infections associated with MS may induce axonal damage first, leading to demyelination second (Inside-Out model). Most likely, there is a balance of the Outside-In and Inside-Out processes depending on the model or disease subtype of MS. The Inside-Out model may initially drive the disease, leading to myelin antigen presentation in the brain and stimulation of Outside-In responses, which result in further damage to axons, setting up a cycle of pathology involving both pathways.

Public Health Relevance

Axonal damage in multiple sclerosis (MS) contributes to permanent neurological deficits. Therefore, it is important to understand the mechanisms of axonal damage. This project seeks to elucidate a potential beneficial versus detrimental role of axonal degeneration and its relationship to inflammation and demyelination, using viral and autoimmune models for MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS059724-03
Application #
7690706
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2008-09-30
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$192,281
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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