Monday, 11 December 2017

An internal cell signalling molecule found to support remyelination

Do you want to know about cell signalling and how the oligodendrocyte knows when to make myelin or not?

The protein tyrosine phosphatase Shp2 regulates oligodendrocyte differentiation and early myelination and contributes to timely remyelination. Ahrendsen JT, Harlow DE, Finseth LT, Bourne JN, Hickey SP, Gould EA, Culp CM, Macklin WB. J Neurosci. 2017 pii: 2864-16.

Shp2 is a nonreceptor protein tyrosine phosphatase that has been shown to influence neurogenesis, oligodendrogenesis, and oligodendrocyte differentiation. Furthermore, Shp2 is a known regulator of the Akt/mTOR and ERK signaling pathways in multiple cellular contexts, including oligodendrocytes. Its role during later postnatal CNS development or in response to demyelination injury has not been examined. Based on the current studies, we hypothesize that Shp2 is a negative regulator of CNS myelination. Using transgenic mouse technology, we show that Shp2 is involved in oligodendrocyte differentiation and early myelination, but is not necessary for myelin maintenance. We also show that Shp2 regulates the timely differentiation of oligodendrocytes following lysolecithin-induced demyelination, although apparently normal remyelination occurs at a delayed time point. These data suggest that Shp2 is a relevant therapeutic target in demyelinating diseases such as multiple sclerosis.

SIGNIFICANCE STATEMENT In the present study, we show that the protein phosphatase Shp2 is an important mediator of oligodendrocyte differentiation and myelination, both during developmental myelination as well as in myelin regeneration. We provide important insight into the signaling mechanisms regulating myelination and propose that Shp2 acts as a transient brake to the developmental myelination process. Furthermore, we show that Shp2 regulates oligodendrocyte differentiation following demyelination and therefore has important therapeutic implications in diseases such as multiple sclerosis
                                     Expression from Brain seq
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), SHP-2, or protein-tyrosine phosphatase 2C (PTP-2C) is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. 

This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. 

Mutations in this gene are a cause of Noonan syndrome and Leopard syndrome as well as acute myeloid leukemia.

Is this going to be a good target for remyelination without side-effects, one would think this will be unlikely as the molecule is expressed at high levels all over the place. 

This feature seems to be common for many of the remyelination .pathways. However do we need to treat long term or give a pulse treatment?

We dont know...becuase we are not testing for this. The models used naturally repair without any treatment so all we are seeing in an enhanced repair. People never look at what happens in a model where there is chronic demyelination yet we jump from these simple models straight into human trials.

Is it surprising that we often struggle to see benefit.

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