Strategies for the regeneration of myelin

Date:
November 4, 2021
Source:
Max-Planck-Gesellschaft
Summary:
New production or recycling of cholesterol: The duration of the
disorder makes all the difference.



FULL STORY ==========================================================================
The degradation and regeneration of myelin sheaths characterise
neurological disorders such as multiple sclerosis. Cholesterol is
an indispensable component of myelin sheaths. The cholesterol for
the regenerated myelin sheaths must therefore either be recycled from
damaged myelin or produced again locally. In a recent study, scientists
at the Max Planck Institute for Experimental Medicine in Go"ttingen,
led by Gesine Saher, found that in the case of chronic damage, unlike
in acute damage, hardly any cholesterol is recycled. Instead, the new production of cholesterol determines the efficiency of the repair.

Unexpectedly, not only the myelin-forming cells themselves but also
nerve cells make an important contribution to regeneration. Cholesterol synthesis in nerve cells ensures the replenishment of newly myelin-forming cells. This could impact the therapeutic success for myelin disorders
such as multiple sclerosis.


==========================================================================
When lesions develop in myelin disorders such as multiple sclerosis,
the cholesterol- and lipid-rich insulating layer around the nerve fibres
is lost.

In order to prevent permanent damage, the now unmyelinated nerve fibres
must be protected again as quickly as possible by newly regenerated
myelin. In the acute phase of the disorder, defective myelin is
abundant. Cholesterol is taken up from defective myelin by phagocytes
and reprocessed and made available to the myelin-forming cells. This
repair process often proceeds quickly and smoothly in younger patients.

However, the longer the disorder lasts, the less efficient this critical process becomes. Phagocytes of the brain can turn into foam cells that
are no longer involved in the recycling of cholesterol. The chronic and repeated degradation of myelin sheaths eventually leaves nerve fibres permanently unmyelinated. Degenerated myelin and cholesterol are thus
scarce in chronic lesions. "We suspected that in the low-cholesterol environment of chronic lesions, the production of this important lipid
kicks in," explains lead researcher Gesine Saher from the Max Planck
Institute for Experimental Medicine in Go"ttingen.

Cholesterol from nerve cells promotes the regeneration of myelin-forming
cells Saher and her working group are investigating the role
of cholesterol and other lipids in the nervous system under both
physiological and pathological conditions. Together with an international
team of researchers, they have now investigated which of the body's own processes contribute to repair after chronic myelin disease.

In their study, the researchers examined nerve cells (neurons) from pharmacological and genetic mouse models with myelin defects. Neurons
normally cover the majority of their cholesterol demand by uptake of
lipid-rich lipoproteins with only little synthesis. In acute lesions, cholesterol production in nerve cells is even further reduced. "The fact
that the neurons from the chronic disorder models boost the production
of cholesterol was completely surprising," reports Stefan Berghoff,
former coworker of Gesine Saher and first author of the study.

In order to investigate the relevance of this observation, the researchers genetically inactivated the synthesis of cholesterol in neurons and in
the myelin-forming cells (oligodendrocytes) of mice. In the neuronal and oligodendroglial mutants, the regeneration of myelin sheaths was severely reduced in chronic lesions. However, unlike in glial mutants, neuronal cholesterol also enhanced the proliferation of oligodendrocyte progenitor cells. Treatment with a cholesterol-enriched diet had a similarly positive effect on these progenitor cells. "We assume that neurons provide this
extra production of cholesterol," says Berghoff. "This benefits all
other cells in chronic lesions, which have greatly reduced their own
production of cholesterol." Although acute and chronic lesions and
their endogenous repair mechanisms differ greatly, the availability and management of cholesterol and other lipids ultimately makes a considerable contribution to the efficiency of regeneration.

"The challenge of the next studies will be to develop therapy concepts
for patients with myelin disorders in which acute and chronic lesions
can be treated simultaneously," says Saher, leader of the research team.

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Stefan A. Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Constanze
Depp,
Andrew O. Sasmita, Martina H. Vasileva, Patricia Scholz, Yu Zhao,
Dilja Krueger-Burg, Sven Wichert, Euan R. Brown, Kyriakos Michail,
Klaus-Armin Nave, Stefan Bonn, Francesca Odoardi, Moritz Rossner,
Till Ischebeck, Julia M. Edgar, Gesine Saher. Neuronal cholesterol
synthesis is essential for repair of chronically demyelinated
lesions in mice. Cell Reports, 2021; 37 (4): 109889 DOI:
10.1016/j.celrep.2021.109889 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211104115248.htm

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