*MS Article* Researchers find cellular signal that aggravates MS

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http://www.news-medical.net/?id=19309

Researchers discover a cellular signal that aggravates the symptoms of

multiple sclerosis

Medical Research News Published: Sunday, 6-Aug-2006

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Depression, coordination and speech problems, muscle weakness and

disability are just a few of the symptoms of Multiple Sclerosis (MS).

Researchers from the Mouse Biology Unit of the European Molecular

Biology Laboratory (EMBL) in Italy and the Department of

Neuropathology at the Faculty of Medicine, University of Gvttingen,

Germany, have now discovered that these symptoms are aggravated by a

specific signal in cells in the nervous system.

The study, which will appear in this week's online issue of Nature

Immunology, suggests that blocking the proteins that regulate the

signal might be an efficient strategy for new therapies against MS.

Nerve cells in our brain and spinal cord communicate with each other

using electrical signals. This communication is fast and efficient

because - just like wires in an electrical circuit - the axons of our

nerves are surrounded by an insulating layer. In MS this protective

sheath, made up of a mixture of lipids and proteins called myelin,

gets destroyed by cells of our own immune system, and the

communication between nerve cells gets disrupted. A central player in

the molecular mechanisms behind MS is a signaling molecule called NF-kB.

" We have known for a long time that NF-kB is crucially involved in

MS, " says Manolis Pasparakis, a former Group Leader at EMBL's Mouse

Biology Unit who now works as a Professor at the Institute for

Genetics at the University of Cologne, " but until now it was not clear

if it was friend or foe. We were not sure whether it protects the

brain cells against the consequences of the disease or actually

aggravates the damage. "

To get a clear picture of NF-kB's role in MS, Pasparakis and his

scientific collaborators at the University of Gvttingen investigated

what happens to mice with an MS-like condition if the action of NF-kB

is blocked. To shut down the signal they inactivated IKK2 and NEMO,

two proteins that activate NF-kB.

" This was quite a challenge because NF-kB is involved in many crucial

processes throughout the entire body, and shutting down its activation

in all cells kills the mouse before it is born, " says Pasparakis, " To

observe the effect of NF-kB in MS, we used sophisticated genetic

techniques to generate mice that do not express IKK2 and NEMO in brain

cells only. "

The results were mice that showed much milder MS symptoms than normal,

an effect that is very likely to be linked to the lower amount of

inflammatory messengers produced by their brain cells.

" NF-kB regulates the production of messengers that are released during

inflammation to recruit and activate immune cells, " says Marco Prinz,

whose group at the University of Gvttingen collaborated in the

research. " Generally this is a good strategy to protect the body from

infections. But in MS it is exactly these immune cells that cause the

problem and their hyperactivation through NF-kB only makes the

situation worse. "

Blocking IKK2 and NEMO interfered with this pathological action of

NF-kB and alleviated the symptoms of MS. This makes the proteins

promising as potential drug targets for new therapies against the

disease. The human NF-kB signaling network is very similar to that of

mice, so that compounds that inhibit IKK2 and NEMO are likely to lead

to the same alleviation of symptoms in humans.

http://www.embl.de