Sunday, 22 June 2014

A molecule that blocks remyelination

Tepavčević V, Kerninon C, Aigrot MS, Meppiel E, Mozafari S, Arnould-Laurent R, Ravassard P, Kennedy TE, Nait-Oumesmar B, Lubetzki C.Early netrin-1 expression impairs central nervous system remyelination. Ann Neurol. 2014 Jun. doi: 10.1002/ana.24201. [Epub ahead of print]

Objective: Chronically demyelinated multiple sclerosis (MS) lesions are frequently characterized by scarce undifferentiated oligodendrocyte progenitor cells (OPCs) suggesting the exhaustion of a local OPC pool followed by failure of recruitment and differentiation. Stimulating prompt OPC recruitment following demyelination could improve myelin repair by providing sufficient numbers of remyelinating cells during the "repair-permissive" period. Understanding mechanisms that determine this process may have important therapeutic implications. 
We therefore investigated the role of the guidance molecule netrin-1 in OPC recruitment and CNS remyelination. 
Methods: Netrin-1 expression was analysed immunohistochemically in different types of MS lesions and in the murine lysolecithin model of demyelination. The influence of netrin-1 on CNS remyelination was examined using gain and loss of function experiments. 
Results: We show that in MS lesions, astrocytes upregulate netrin-1 expression early during demyelination and netrin-1 receptors are expressed by OPCs. In contrast, in the efficiently-repairing lysolecithin model of demyelination (astrocyte-free), netrin-1 expression is absent during early phases and detected concomitant with completion of OPC recruitment. In vitro migration assays demonstrated that netrin-1 is a chemorepellent for migrating adult OPCs. In mouse lesions, antibody-mediated disruption of netrin-1 function at the peak phase of recruitment increased OPC numbers. On the other hand, experimental induction of netrin-1 expression prior to OPC recruitment reduced the number of cells recruited and impaired remyelination. Interpretation: Our findings support the conclusion that netrin-1 expression within demyelinating MS plaques blocks OPC recruitment, which with repeated demyelinating episodes contributes to permanent remyelination failure.
Demyelination appears to result from both the failure of immature oligodendrocytes to develop into myelinating cells or that there are not enough myelinating cells in the area of demyelinating. This study suggests that netrin blocks the recruitment of myelinating cells. Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides."Netrins are chemotropic; a growing axon will either move towards or away from a higher concentration of netrin. Netrin attraction is mediated through UNC-40/DCC cell surface receptors and repulsion is mediated through UNC-5 receptors. Netrins also act as growth factors, encouraging cell growth activities in target cells. Therefore, if we can find effective netrin blockers this may be useful for repair

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