Tuesday, 8 September 2015

Pleiotrophin for remyelination

Kuboyama K, Fujikawa A, Suzuki R, Noda M.Inactivation of Protein Tyrosine Phosphatase Receptor Type Z by Pleiotrophin Promotes Remyelination through Activation of Differentiation of Oligodendrocyte Precursor Cells. J Neurosci. 2015;35(35):12162-71. doi: 10.1523/JNEUROSCI.2127-15.2015

Multiple sclerosis (MS) is a progressive neurological disorder associated with myelin destruction and neurodegeneration. Oligodendrocyte precursor cells (OPCs) present in demyelinated lesions gradually fail to differentiate properly, so remyelination becomes incomplete. Protein tyrosine phosphatase receptor type Z (PTPRZ), one of the most abundant protein tyrosine phosphatases expressed in OPCs, is known to suppress oligodendrocyte differentiation and maintain their precursor cell stage. In the present study, we examined the in vivo mechanisms for remyelination using a cuprizone-induced demyelination model. Ptprz-deficient and wild-type mice both exhibited severe demyelination and axonal damage in the corpus callosum after cuprizone feeding. The similar accumulation of OPCs was observed in the lesioned area in both mice; however, remyelination was significantly accelerated in Ptprz-deficient mice after the removal of cuprizone. After demyelination, the expression of pleiotrophin (PTN), an inhibitory ligand for PTPRZ, was transiently increased in mouse brains, particularly in the neurons involved, suggesting its role in promoting remyelination by inactivating PTPRZ activity. In support of this view, oligodendrocyte differentiation was augmented in a primary culture of oligodendrocyte-lineage cells from wild-type mice in response to PTN. In contrast, these cells from Ptprz-deficient mice showed higher oligodendrocyte differentiation without PTN and differentiation was not enhanced by its addition. We further demonstrated that PTN treatment increased the tyrosine phosphorylation of p190 RhoGAP, a PTPRZ substrate, using an established line of OPCs. Therefore, PTPRZ inactivation in OPCs by PTN, which is secreted from demyelinated axons, may be the mechanism responsible for oligodendrocyte differentiation during reparative remyelination in the CNS.
SIGNIFICANCE STATEMENT:Multiple sclerosis (MS) is an inflammatory disease of the CNS that destroys myelin, the insulation that surrounds axons. Associated damages to oligodendrocytes (the cells that produce myelin) and nerve fibres produce neurological disability. Most patients with MS have an initial relapsing-remitting course for 5-15 years. Remyelination during the early stages of the disease process has been documented; however, the molecular mechanism underlying remyelination has not been understood. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a receptor-like protein tyrosine phosphatase preferentially expressed in the CNS. This study shows that pleiotrophin, an inhibitory ligand for PTPRZ, is transiently expressed and released from demyelinated neurons to inactivate PTPRZ in oligodendrocyte precursor cells present in the lesioned part, thereby allowing their differentiation for remyelination.


So you can read the authors view. The big question is whether there there this target is druggable. As it is is a signalling molecule inside the cell then other cells also use such molecules for their own purposes and whilst it is restricted to the CNS they use pleiotrophin and as its name suggests it can do many things....remyelinate but could there be side effects.

9 comments:

  1. This remyelination mechanism promoted by pleiotrophin act on what stage of the lesions? Only in more recent injuries or old injuries have consolidated? This is a naive question that I have whenever I read some article on remyelination ...

    ReplyDelete
    Replies
    1. No animal study has ever looked at old lesions

      Delete
    2. Thanks MD, deep down I guessed it already ... I would like to see a study of this direction with old injuries, but if it's too difficult to promote remyelination of recent injuries, old injuries then "not even speak" ...Ir has a brazilian athlete who became quadriplegic during practice for the Winter Olympics last year, she is being treated with stem cells in the USA, but the results are still all very "shy" ...

      Delete
    3. it is amazing that we do not dro these experiments but is it fear of the fail... but if we try in ms and fail it will be useless animal experimemts again but science does not try to disprove anymore when it could. All the remyelination trials have this problem.

      Delete
  2. I think Cinara's question is spot on. I also wonder how helpful remyelination drugs/therapies would be for people with progressive MS. For example, I expect the large, troublesome lesion I have on my spine, which has been there for at least 15 years now, is covered in some sort of scar tissue. But it would be the same with neuroprotectives, I would imagine - the benefit would be in stopping or slowing further damage?

    ReplyDelete
    Replies
    1. Yes, that's the idea, it's to try and protect the remaining nerves.

      Delete
  3. if we could remyelinate, would a new coat of myelin halt neuro degeneration?

    ReplyDelete
    Replies
    1. Aidan, my question back to you is does insulating a rusting pipe help to prevent the pipe crumbling? Probably not if you leave it too late.

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.