Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis?
Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, et al.;
Commented by , 21 Oct 2002
Background
Treatment strategies in MS have so far focused on immunomodulatory drugs, although other potential strategies, such as stimulation of the remyelination process, seems promising to explore. Although myelin repair mostly fails in MS lesions, spontaneous partial remyelination may occur in so-called shadow plaques.
The current study deals with the polysialylated form of the neural cell adhesion molecule NCAM, PSA-NCAM, which at the surface of axons acts as an inhibitor of myelination. Disappearance of PSA-NCAM from the axonal surface during development initiates myelination, and is still absent in most areas of the adult brain, except in restricted areas which exhibit neurogenesis and/or plasticity.
Aim
To investigate if demyelinated axons can recapitulate PSA-NCAM re-expression, which might act as an inhibitor of remyelination in MS.
Methods
The authors analyzed frozen post-mortem brain tissue from 24 MS patients. A total of 40 lesions were analyzed and among these 30 consisted of plaque and periplaque and 10 were identified as shadow plaques. The course of MS was secondary progressive (9), primary progressive (6) or relapsing-remitting (1).
In eight cases the course of the disease was not specified. Controls consisted of post-mortem brain tissue from patients with amytrophic lateral sclerosis (2) or without neurologic disease (3). The brains were sliced coronally in 1cm thick slices and analyzed by immunohistochemistry.
Results
All plaques were classified as chronic by histological methods. In two cases axon loss was prominent in the plaque. In the other cases there were a relative preservation of axons, although histological signs of axonal dysfunction were prominent.
In 27 plaques the authors detected positive PSA-NCAM immunolabeling on axons. In three cases no PSA-NCAM was detected in the plaque. In two of these axonal loss was severe. Furthermore it was shown that PSA-NCAM was restricted to axons with intermediate or low levels of phosphorylation. PSA-NCAM expression was also detected on astrocyte cell bodies and processes within the plaque.
In the five control cases there were some immunoreactivity on astrocytes but not on axons. In the shadow plaques PSA-NCAM reactivity was never observed on the remyelinated internodes, but was restricted to demyelinated axons.
Discussion
PSA-NCAM is believed to play a critical role in nervous system plasticity, since the molecule presumably delays or inhibits the myelin forming cells to attach to the axon. The re-expression of PSA-NCAM is caused by a reappearance of sialyltransferase activity on a transcriptional and non-transcriptional level. The authors hypothesize that the mechanism involved in PSA-NCAM re-expression on demyelinated/dysfunctional axons, is related to activation of calcium ion channels.
The fact that the same axons showed low levels of phosphorylation, supports the view that the PSA-NCAM re-expression could be part of a plasticity response, or a more general developmental program. Unfortunately this causes remyelination to fail. In the shadow-plaques PSA-NCAM was not expressed on remyelinated axons, but why this possible downregulation or non-expression of the molecule occurs remain unanswered.
The study describes a potentially important inhibitory signal of remyelination, and might encourage research in new treatment strategies in MS.