Monday, 11 December 2017

Temperature dependence of impulse conduction in optic nerve axons



Thanks for the comments
We were grateful when a number of readers responded to our enquiry regarding temperature dependent symptoms in MS, and we learned more about how people cope with the symptoms. Following this conversation, I thought it worthwhile to draw attention to a paper we recently published, that suggests that there are functional differences between normal peripheral and central axons, and these differences provide a new view on temperature sensitivity.   

Optic nerve amazingly sensitive to changes in temperature
A few years ago, my colleagues and I found unexpectedly that the function of rodent optic nerve axons, maintained in a nerve bath, is amazingly sensitive to temperature changes. The nerve bath that we use is a chamber in which a nerve can be maintained with nutrient and oxygen outside the body. The comparison we were subsequently able to make with normal sensory axons in the human hand in vivo, with a colleague at the University of Sydney, makes it look like the phenomenon is one that affects the optic nerve (and therefore potentially central axons more generally) but not the peripheral nerve. One of the advantages of doing experiments in a nerve bath is that one can control temperature really precisely, and also the application of drugs to the tissue. Since then we have tried to confirm that the temperature sensitivity really exists, and we have done it a number of ways now, so at least in terms of our experimental preparation there seems little doubt it exists, and secondly we have been trying to find out what the mechanism of such sensitivity might be. This is the paper: Diuretic-sensitive electroneutral Na+ movement and temperature effects on central axons by Meneka Kanagaratnam, Christopher Pendleton. Danilo Almeida Souza, Joseph Pettit, James Howells and Mark Baker. Journal of Physiology 595.11 (2017) 3471-3482.

Ideas about the mechanism of temperature sensitivity
The way I became aware of temperature dependent symptoms was initially through the work of Hugh Bostock, where he used a peripheral nerve model of demyelination, and demonstrated conduction failure in single axons when raising temperature acutely. There is a classical explanation for this, based on work done by the Nobel Prize winners, Alan Hodgkin and Bernard Katz. The classical explanation says that the nerve impulse gets briefer when the axon warms up, and this brevity means that the impulse is more likely to fail at sites along the axon that have been damaged by demyelination. Of course, there is every expectation that this principle is still likely applicable, but what we have found suggests that normally in central axons, as one warms up, the axons get less excitable in a way unrelated to the brevity of the impulse but for another reason. It is because the warming alters the resting properties of the axon, making an impulse harder to generate and also harder to propagate (ie to jump along). In normal axons, this effect of warming we would suggest is within the tolerance of the nervous system, and symptoms don’t appear. (That said, it is common knowledge that relatively minor rises or falls in core body temperature in fit and healthy people can dramatically alter properties of the nervous system, including causing loss of conscious for example with hypothermia). So we could now offer an additional insight and say that where impulse conduction is touch-and-go at sites in damaged axons, one possibility is that this newly described property could contribute to make the impulse fail, and so exacerbate symptoms. We are still working on the biophysical mechanism, and once we have more confidence in that mechanism it is our hope that a route to pharmacologically manipulating the property will become apparent, and so in the future more help may be offered to people experiencing temperature dependent symptoms. 

Do you have temperature dependent symptoms that affect your vision? Those were the first temperature dependent symptoms described. Perhaps you have double vision, perhaps altered acuity? How does getting too warm affect your vision? We would value your comments
Thank you!

Mark Baker

Education: What do antibodies do

You have full text access to this OnlineOpen article
Prospects from systems serology research
Kelly B. Arnold and Amy W. Chung
Version of Record online: 1 DEC 2017 | DOI: 10.1111/imm.12861

An internal cell signalling molecule found to support remyelination

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.

Sunday, 10 December 2017

Measuring Hand Function

Online monitoring of hand function. Are you up for doing the BRAIN test or will the cardboard 9HPT do the job? 



Saturday, 9 December 2017

Relapse without cell depletion in the blood

As you may be aware I have been banging on about the importance of B memory cells for most of the year, but it has been an uphill struggle to get this view accepted. 

However, response to therapy creates a powerful piece of insight that frankly can't be ignored. But I meet Ostriches ever day.




Friday, 8 December 2017

Fingolimod: does it help with upper limb function?

ProfG G has been been saying that we should #Thinkhand and target hand function for outcomes in clinical trials. This idea may be supported by studies with ocrelizumab and natalizumab but there are a couple of exceptions.

Thursday, 7 December 2017

Reflections on the ECF 2017

I have just returned from the European Charcot Foundation meeting in Baveno, Italy. The meeting is small (< 500 attendees) with no parallel sessions and ample time to mix with attendees and chew the cud. I did a plenary presentation on "dealing with increasing economic constraints".  The feedback I received after my talk, and subsequently via email, has been extraordinary. An eminent neurologist said he was glad that someone was thinking about these issues and taking it on. I have also been contacted by a health economist and have been urged to write up the talk.




Wednesday, 6 December 2017

Yet more data supports the B memory Cell idea

I can hear you saying, "Oh no not another B-cell paper!". However, this is where the action is. It is the B-cell and not the T-cell. Do you agree or disagree? Have your say. 


Tuesday, 5 December 2017

Blood cancers after fingolimod treatment

How immunosuppressive is fingolimod? Does fingolimod's longterm immunosuppression result in an increased cancer risk? 

Monday, 4 December 2017

Guest Post: an update from Saúl Reyes

It has been a while since I last wrote a post for this blog and figured it was time to update you all! I have recently completed my training with Professor Giovannoni and it really confirmed my desire to pursue a career in MS. I am back home in Colombia just getting ready to finish my residency in Neurology. I am incredibly grateful for the time I spent with the Barts and The London Neuroimmunology Group. Every member of the team was very passionate about MS and brought that excitement to teach me. I am delighted to be able to keep in touch with you all through this blog. Please enjoy my new post and don't forget to leave your comments below!