Nerves Under Control: Potential Treatment for Charcot-Marie-Tooth Disease

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http://www.sciencedaily.com/releases/2010/05/100518112649.htm

Nerves Under Control: Potential Treatment for Charcot-Marie-Tooth Disease

ScienceDaily (May 18, 2010) — The proper transmission of nerve signals along

body nerves requires an insulation layer, named myelin sheath. To be efficient

this sheath is designed to have a certain thickness and researchers from the ETH

Zürich have now discovered that proteins Dlg1 and PTEN interact to control the

myelin sheath thickness. Recently published in Science their discovery improves

our understanding of Charcot-Marie-Tooth neurodegenerative diseases and open a

new avenue in the potential treatment of these incurable and debilitating

diseases.

A crucial factor in the transmission of nerve signals is the myelin layer --

also known as the myelin sheath -- which surrounds the axons. Axons are nerve

cell projections through which the signals are relayed; the myelin sheath is

formed by the Schwann cells in the peripheral nervous system, i.e. in the

nervous system outside the brain and spinal chord. If it is too thick or too

thin, the signal transmission slows down; if the myelin sheath becomes too badly

damaged, it can cause diseases like Charcot-Marie-Tooth diseases. Patients

suffer from an increasing weakness of the hands and feet, which gradually

spreads to the arms and legs, sometimes even making them wheelchair-bound for

the rest of their lives.

But which molecules regulate the thickness of the myelin sheath? Scientists at

ETH Zurich from the research groups around biologists Ueli Suter and Nicolas

Tricaud set about finding out. They have now published their findings in an

online article in the journal Science.

The scientists didn't have to start their search entirely from scratch, however,

having already developed a mouse model for a sub-type of Charcot-Marie-Tooth

disease; the model is based upon a mutation in the gene for the protein MTMR2

and leads to hypermyelination by the Schwann cells. What's more, the researchers

already knew from other studies that MTMR2 interacts with Dlg1.

In experiments conducted on cell cultures and the sciatic nerve in mice, the

researchers were now able to demonstrate that Dlg1 inhibits myelin growth. For

this to work, however, it needs to enlist the help of another signal protein:

PTEN. Together, they ensure that the growth of the myelin sheath does not go to

excess in the mouse's development. If the brake is " released " by suppressing

Dlg1 or PTEN, it results in myelin excess that not only leads to an extra-thick

myelin sheath, but also to its degeneration. This process is characteristic of

various diseases of the peripheral nervous system and , as it was revealed in

the mouse model of Charcot-Marie-Tooth disease the Dlg-PTEN brake no longer

works in these diseases. Nicolas Tricaud is convinced that the project helps to

understand the basic molecular mechanisms of myelination, as well as offering

new opportunities to define how the misdirection of these processes can cause

neurodegenerative diseases and how this might be remedied.