21 May 2013

Is SIRT1 deacetylase the cause of multiple sclerosis?

Multiple Sclerosis and SIRT1

LifeSciencesToday based on materials from Stanford University School of Medicine:
Blocking protein expression delays onset of multiple sclerosis in mice, study says

According to the results of a study conducted by scientists at the Stanford University School of Medicine, blocking the expression of just one protein in brain cells delays the onset of paralysis in mice with a form of multiple sclerosis.

Why this is happening is still unclear. It is possible, in particular, that blocking the expression of this protein – SIRT1 deacetylase involved in energy metabolism – enhances the formation of cells that create an insulating myelin sheath necessary for the transmission of nerve signals and damaged in autoimmune diseases such as multiple sclerosis and Guillain-Barre syndrome.

Although scientists emphasize the need for additional research, their findings suggest that self-healing of the brain of patients with myelin-associated diseases or injuries may be possible through selective intervention in the function of SIRT1.

"[The results of the study] are very interesting because SIRT1 activation is generally considered beneficial for health and metabolism, but in this case its inactivation can provide protection against demyelination," says Anne Brunet, PhD, associate professor of genetics.

Dr. Brunet, who is also a researcher at the Stanford Cancer Institute, is the senior author of an article about this study published in the journal Nature Cell Biology (Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain).

Blocking SIRT1 expression appears to work by stimulating differentiation of neural brain stem cells into oligodendrocyte progenitor cells. These cells, in turn, become mature oligodendrocytes that wrap the long processes of neurons with myelin, a fatty substance that provides interneuronal transmission of electrical impulses. In humans, myelination mainly occurs in infancy and adolescence.

Oligodendrocytes (marked yellow), myelinating axons (marked green).
Photo: courses.stu.qmul.ac.uk .

By damaging the protective myelin coating and impeding interneuronal communication, diseases such as multiple sclerosis wreak havoc in the central nervous system.

Since the expression level of SIRT1 is higher in the brains of mice with an induced form of multiple sclerosis, Dr. Brunet and her colleagues wondered what role this protein could play in the formation or suppression of oligodendrocytes. To get an answer, they created laboratory mice in which, when tamoxifen is administered, the function of the SIRT1 coding gene in neural stem cells is selectively disrupted.

It turned out that over time, a subpopulation of neural stem cells with suppressed SIRT1 expression began to produce proteins characteristic of oligodendrocyte progenitor cells, and eventually became similar to typical oligodendrocytes. Neural stem cell culture showed similar results. Genetic modification of cells (suppression of the activity of the SIRT1 gene), as well as treatment of unmodified cells with a drug specifically inhibiting the activity of the SIRT1 protein, resulted in a noticeable increase in the proportion of cells expressing a marker protein specific to oligodendrocytes.

Suppression of SIRT1 expression contributed to a faster recovery of mice after administration of a compound that causes demyelination of neurons. In addition, for some time they were protected from paralysis, which develops as a result of a disease close to multiple sclerosis.

"Our work shows that SIRT1, in principle, can limit the proliferation of oligodendrocyte progenitor cells and that it needs to be inactivated to temporarily increase the number of these myelinating cells," says Dr. Brunet.

To better understand the function of SIRT1 in brain cells, scientists have identified a set of genes whose expression increases when it is suppressed. It turned out that such genes include several of the growth factors involved in signaling, cellular metabolism and protein synthesis. One of them – PDGFR-alpha (platelet-derived growth factor receptor alpha) – activates two signaling pathways. Blocking these pathways significantly inhibits the growth of oligodendrocyte progenitor cells observed during SIRT1 inactivation.

Identification of target enzymes of drugs regulating the regeneration of oligodendrocytes may contribute to the development of methods for the treatment of demyelinating injuries and diseases such as multiple sclerosis.

"Our study shows that it is possible to increase the population of oligodendrocyte progenitor cells by pharmacological action at several points of this pathway," says Dr. Brunet. "Such approaches can be of great importance for regenerative medicine."

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