Tuesday, 8 January 2013

Research: nerve break down products are signal to start repair

#MSBlog: The release of proteins from damaged  nerve fibres stimulates repair processes in particular oligodendrocytes. How relevant is this to progressive MS?

Fressinaud C, Eyer J. Axoskeletal proteins prevent oligodendrocyte from toxic injury by upregulating survival, proliferation, and differentiation in vitro. Neurochem Int. 2012 Dec. doi:pii: S0197-0186(12)00410-X. 10.1016/j.neuint.2012.12.012.

Background: Neurofilaments (NF) are detected in the cerebrospinal fluid of MSers, and their concentration correlates with disease severity. These investigators have recently demonstrated that NF and co-isolated proteins increase the proliferation and differentiation of oligodendrocytes (OL) in the laboratory. 


"Neurofilaments are the structural or scaffolding proteins with nerve processes. They dictate the size of the nerve fibres and are released when nerve fibres, in particular axons, are damage."

Objective: If these proteins are released in the extracellular environment in MS, they might then regulate remyelination by OL. To test this hypothesis they took advantage of a paradigm of OL toxic injury using lysophosphatidyl choline (LPC), which decreases proliferation and differentiation of surviving cells, and destroys myelin-like membranes. 

"LPC is a toxic to myelin and causes it to breakdown. This is one of  the common demyelinating models used to study demyelination followed by remyelination in the laboratory."

Methods and results: In OL cultures that have been treated with LPC, NF fractions as well as tubulin (TUB) significantly improved recovery: the number of OL progenitors (OLP, A2B5+ cells) increased by 100% and their proliferation by 200%, whereas differentiated (CNP+) and mature (MBP+) cells increased by 150% compared to cultures treated with LPC alone. When added at the time of LPC treatment, NF and TUB protected OL from LPC toxicity; they increased OLP by 90%, as well as the number of CNP+ and MBP+ OL by 65 to 110% respectively, compared to cultures treated only with LPC. These effects were specific since irrelevant proteins (actin, skin proteins) were ineffective. 

Conclusion: This demonstrates that NF and TUB protect OL and increase OLP proliferation, as well as their survival, when challenged with LPC, without delaying differentiation and maturation in vitro. Thus, NF and TUB delivered following axonal damage in MS could participate in the regulation of remyelination through this process.

Neurofilaments stained green within neuronal processes. 

"This study makes a lot of sense from a biological perspective  i.e. proteins that are released from damage nerve cells then stimulate surrounding cells to repair the damage. In other words nature has built in signal for repair. What you may or may not know is that some MSers mount an immunological challenge to neurofilaments and make antibodies to the protein. Antibodies are responsible for mopping up proteins and targeting them to scavenger cells so that that can be cleared. MSers with with progressive disease tend to have higher levels of antibodies to neurofilament. I wonder if these antibodies are blocking the repair or recovery signals that neurofilaments provide to oligodendrocytes? This may be another mechanism underlying progressive MS."

"The following is a study I was involved several year ago looking at antibodies to neurofilaments in MSers."

Eikelenboom et al. Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy. Neurology. 2003 Jan 28;60(2):219-23.

OBJECTIVETo evaluate markers of axonal damage in CSF and serum of MSers with different subtypes of MS in relation to measures of disease progression on MRI.

METHODS: In 51 MSers (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions).

RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures.

CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.

Differing degrees of brain atrophy in a RRMSer (B) compared to an MSer with progressive disease (C). Could anti-NF antibodies be responsible for driving brain atrophy? Please note the healthy control on the left (A).

"We can now interpret the results of this study in a completely different light. This is how science evolves."

"If we prevent MSers from developing antibodies to neurofilaments would we improve their outcome? Would they have better recovery mechanisms?"

12 comments:

  1. Hope so. Please hurry up. SPMS moving on and I have stuff to do! :-/ HNY Pam

    ReplyDelete
  2. Only being anonymous because can't get post to work otherwise..Pam

    ReplyDelete
  3. Agree with Pam - good to se another line for possible therapy :-)

    ReplyDelete
    Replies
    1. This idea may lead to something patients can use in 20-30 years. Let's hope it helps patients in the future, it's no good for us.

      Delete
    2. Not necessarily, you don't know if one of the new neuro-protective compounds doesn't target these antibodies - perhaps they do without the researchers knowing the exact mechanism? Or there is a drug already in use for something else that has not been tested in MS but is capable of blocking anti-bodies? Don't be so negative, you are not helping anybody with it.

      Delete
    3. Anonymous Tuesday, January 08, 2013 1:07:00 PM

      Killjoy!

      Delete
    4. What do ProfG/MD say?

      Delete
    5. from 'Anonymous Tuesday, January 08, 2013 1:07:00 PM' again:

      I thought I was being realistic, not negative at all. Re-read MD's series on turning an idea into a treatment.

      http://multiple-sclerosis-research.blogspot.com/2011/08/drug-game.html
      http://multiple-sclerosis-research.blogspot.com/2011/08/drug-game-part-ii_05.html
      http://multiple-sclerosis-research.blogspot.com/2011/08/drug-game-part-iii_09.html
      http://multiple-sclerosis-research.blogspot.com/2011/08/drug-game-part-iv.html
      http://multiple-sclerosis-research.blogspot.com/2011/08/drug-game-back-agai.html

      Delete
  4. Also, anaon 1:07, surely it depends how old you are and how active MS is?

    ReplyDelete
  5. yes, come on people. It is hard to be positive and today has been tough but keep trying. If you start bringing me and others down as well it will only make things worse. And its flipping raining. This article does sound like good news. Theres only one Prof G and suspect he doesnt get enough time to concentrate for long on any single project. Pam

    ReplyDelete
  6. Is diet a consideration do you think?
    Tracey roffey

    ReplyDelete
    Replies
    1. Diet is important for health, but in this case i have no idea but suspect not

      Delete

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