Mechanisms identified to restore myelin sheaths after injury or in
multiple sclerosis

Date:
August 24, 2020
Source:
Johannes Gutenberg Universitaet Mainz
Summary:
A research team has identified an important mechanism that can
be used to control the restoration of myelin sheaths following
traumatic injury and in degenerative diseases. With the insights
gained, the researchers were able to regenerate damaged myelin
sheaths in mice by treating them with the active substance
theophylline, thereby restoring their nerve cell function.



FULL STORY ==========================================================================
A research team led by neurobiologist Professor Claire Jacob has
identified an important mechanism that can be used to control the
restoration of myelin sheaths following traumatic injury and in
degenerative diseases. With the insights gained, the researchers were
able to regenerate damaged myelin sheaths in mice by treating them with
the active substance theophylline, thereby restoring their nerve cell
function. The groundbreaking findings are the result of research carried
out at Johannes Gutenberg University Mainz (JGU) and the University of
Fribourg in Switzerland.


========================================================================== Neurons are composed of axons, i.e., long fiber-like extensions that
transmit signals to other cells. Many of them are surrounded by a myelin sheath, a thick fatty layer that protects them and helps to transfer
stimuli rapidly. Without myelin, the functional capacity of neurons --
and therefore of the whole nervous system -- is limited and neurons
can easily degenerate. Multiple sclerosis (MS) is one of the diseases associated with myelin sheath degradation. MS patients suffer successive episodes of demyelination resulting in a progressive loss of function
of their nervous system. Remyelination of the axons can prevent this.

The aim is to restore the axons' protective myelin coating Intact
myelin sheaths are a prerequisite for the healthy functioning of the
peripheral and central nervous systems. If the peripheral nervous system
(PNS) is damaged, in an accident involving injury to the arms or legs
for example, the axons and their myelin sheaths can recover relatively
well. "Regeneration of the PNS is quite efficient, although it could
be improved," said Professor Claire Jacob, pointing out that even young
people do not experience complete regeneration.

However, the central nervous system (CNS) is completely different in
this regard as there is no efficient restoration of the axons and
therefore of the myelin sheath after a lesion. This means that CNS
injuries usually result in permanent paralysis -- as in the case of
MS when loss of myelin leads to axon degeneration. MS is the most
common neurodegenerative disease of the CNS and is attributable to
the degradation of the myelin sheath of neurons. The occurrence of
successive lesions can cause permanent loss of function of the CNS if
myelin sheath restoration is inefficient. The capacity of the body to remyelinate decreases dramatically with age. "In order to promote the restoration of myelin, we need to understand the process that controls
the mechanism," emphasized Jacob.

In the recent project, her research group investigated how remyelination
occurs in both peripheral and central nervous systems of mice. "First,
we wanted to understand the process that blocks remyelination. We
subsequently studied how to counteract this blocking effect." The neuroscientists identified a protein called eEF1A1 as a key factor in
the process and found that eEF1A1 activated by acetylation prevents the remyelination process, but if eEF1A1 is deactivated by deacetylation,
myelin sheaths can be rebuilt. The protein that deacetylates eEF1A1 is
the enzyme called histone deacetylase 2 (HDAC2).

Theophylline promotes myelin reconstruction in both peripheral and
central nervous systems "Once we understood this process, we decided
to try to control it by boosting the HDAC2 activity and its synthesis
in cells," said Jacob. This was achieved by using the active substance theophylline, which is also present in tea leaves and has long been used
in the treatment of asthma. In a mouse model, the use of theophylline
over a period of four days resulted in significant recovery.

Restoration of myelin sheaths was particularly impressive in the PNS,
where they recovered completely. Regeneration also improved in the CNS,
as there was rapid and efficient rebuilding of myelin sheaths in both
young and old mice. A low dose of the active substance was sufficient
to trigger the improvements - - a big plus with regard to the known side effects of theophylline, which occur at higher doses.

"In summary, this study [...] shows that theophylline, by activating
HDAC2, promotes eEF1A1 deacetylation, increases [...] remyelination
speed and efficiency after lesion of the PNS and CNS, thus appearing
as a very promising compound to test in future translational studies to accelerate and promote remyelination after traumatic lesions or in the
context of demyelinating disorders," write the authors in their paper
published in Nature Communications. Currently, funding for corresponding clinical trials in patients is being sought, while a patent application
has already been filed.

Professor Claire Jacob has been researching the development of myelin,
axon injuries, and their regeneration for 16 years -- previously at the University of Fribourg in Switzerland and since October 2018 as head of
the Cellular Neurobiology Group at Johannes Gutenberg University Mainz.


========================================================================== Story Source: Materials provided by
Johannes_Gutenberg_Universitaet_Mainz. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Mert Duman, Adrien Vaquie', Gianluigi Nocera, Manfred Heller,
Michael
Stumpe, Devanarayanan Siva Sankar, Jo"rn Dengjel, Dies
Meijer, Teppei Yamaguchi, Patrick Matthias, Thomas Zeis,
Nicole Schaeren-Wiemers, Antoinette Hayoz, Sophie Ruff, Claire
Jacob. EEF1A1 deacetylation enables transcriptional activation
of remyelination. Nature Communications, 2020; 11 (1) DOI:
10.1038/s41467-020-17243-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200824105529.htm

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