Poster Session - Abstract # 22

Investigating Lipid Regulatory Pathways During Demyelination and Myelin Repair Using a Novel Genetic Mouse Model

Nishama D.S Mohotti, Rashmi B. Binjawadagi, Meredith Hartley

Department of Chemistry, University of Kansas, Lawrence, KS, USA

The myelin sheath is a lipid rich membrane that wraps neuronal axons and is discontinuous at the nodes of Ranvier.  This plays a crucial role in the nervous system by acting as an insulating layer facilitating the rapid saltatory impulse conduction of a neuron.  Multiple Sclerosis (MS) is one of the most common central nervous system demyelinating disorder where myelin sheaths are subjected to repeated inflammatory episodes of demyelination resulting in motor disability in patients.  Lipids being the main component in myelin, mapping changes in the lipid profile during myelin damage & repair is capable in identify important lipid pathways that either promote or impair successful remyelination.  Previous studies on identifying lipid regulation during demyelination have been limited by the availability of animal models that feature global demyelination and the ability to correlate myelin damage with disability.  This study features, induced conditional knockout- myelin regulatory factor (iCKO- Myrf) mouse model, which has defined stages of global myelin damage followed by myelin repair that also has a measurable motor disability that correlates with peak demyelination.  Unbiased full profile lipidomics analysis performed on brain and spinal cord samples collected from iCKO-Myrf model have revealed several classes of lipids that change dynamically during demyelination & remyelination.  The largest changes were observed in cholesterol ester (CE) populations with 30-fold increase of CEs in the brain and a delayed 130-fold accumulation of CE in the spinal cord during myelin damage compared to normal physiological conditions.  These results along with behavioral experiments on the iCKO-Myrf model suggest that there is a strong possibility that CE regulatory pathways are highly involved in the myelin damage & repair process.  Therefore, follow-up studies will take the advantage of histology and immunofluorescence coupled with confocal microscopy to identify which CE regulatory pathways are predominantly activated in demyelination and remyelination which will be helpful in developing new therapeutic targets to treat demyelination.