Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination

p57kip2 and ENV act as oligodendroglial inhibitors p57kip2 binds V ‐ATPase providing an interface with ENV‐triggered pathway Anti‐ENV antibody and molecular/pharmacological neutralization of p57kip2/V‐ATPase rescues myelination in presence of ENV AbstractRemyelination in the adult CNS depends on activation, differentiation, and functional integration of resident oligodendroglial precursor cells (OPCs) and constitutes the only spontaneous neuroregenerative process able to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis. The proteins encoded by p57kip2 ‐ and by human endogenous retrovirus type W (pHERV‐W) envelope genes were previously identified as negative regulators of OPC maturation. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved myelin repair. We could demonstrate that myelina tion in vitro is severely affected by this protein but that application of an anti‐ENV neutralizing antibody, currently investigated in clinical trials, can rescue the generation of internodes. We then compared p57kip2 and ENV dependent inhibitory mechanisms and found that a dominant negative vers ion of the p57kip2 protein can equally save OPCs from myelination failure in response to ENV‐mediated TLR4 activation. Additional experiments addressing p57kip2's underlying mode of action revealed a direct interaction with ATP6v1d, a central component of...
Source: Glia - Category: Neurology Authors: Tags: RESEARCH ARTICLE Source Type: research