Myelin, axons and the cells that make them

A nerve cell and its fibre

A nerve cell, or neuron, receives signals through short branches and sends its own signal along one long extension, the axon. Axons are the nerve fibres of the brain and spinal cord, and some run from the brain to the lower spinal cord, a distance of around half a metre.

The signal is a brief electrical pulse called an action potential. It starts when channels in the axon's membrane open and sodium ions rush in. Potassium ions then flow out to reset the membrane. Each patch of membrane that fires triggers the patch next to it, so the pulse travels along the fibre like a flame along a fuse.

What myelin is

In the brain and spinal cord many axons are wrapped in myelin, a sheath made of many layers of cell membrane rolled tightly around the axon. Myelin is mostly fat, which makes it a good insulator, with a few specialised proteins that hold the layers together. Three of them come up again and again in MS research: myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein (MOG). Immune responses against them have been studied as possible drivers of MS for decades, and an antibody against MOG defines a separate disease, MOGAD.[1]

The sheath is not continuous. It is laid down in segments separated by short bare gaps called nodes of Ranvier, where the axon's sodium channels are packed together.

How myelin speeds signals

Because myelin insulates the stretches between nodes, the pulse only needs to be regenerated at the nodes. It seems to jump from one node to the next, which is called saltatory conduction, from the Latin for "to leap". Large myelinated fibres carry signals at up to about 100 metres a second, many times faster than thin fibres without myelin, which manage one or two metres a second. Myelin also saves energy, because after each pulse only the small area of membrane at the nodes has to pump the ions back.[1]

The cell that makes myelin

In the brain and spinal cord, myelin is made by oligodendrocytes. Each oligodendrocyte sends out thin arms that wrap segments of many different axons, often dozens. Nerves outside the brain and spinal cord are wrapped by a different cell, the Schwann cell, and MS spares them. That is why MS affects the eyes, brain and spinal cord but not the nerves in the arms and legs themselves.

The adult brain also contains oligodendrocyte precursor cells, spread evenly through the tissue. They can divide, move to an area that has lost myelin and mature into new oligodendrocytes that wrap bare axons again. This is remyelination, the brain's own repair, and lesson 3.1 follows it in detail.

Myelin feeds the axon

For most of the twentieth century myelin was thought of as insulation and nothing more. Two studies published in 2012 changed that view. They showed that oligodendrocytes pass lactate, a fuel made from sugar, into the axons they wrap, and that mice lose axons when this support is cut off, for example when the lactate transporter MCT1 is removed from oligodendrocytes.[2][3] An axon that loses its myelin therefore loses its insulation and part of its fuel supply at the same time.

What happens when myelin is lost

When MS strips myelin from a stretch of axon, the pulse can slow down, become unreliable or stop at the bare stretch altogether, which is called conduction block. Symptoms appear when enough fibres in one pathway fail together.

Demyelinated axons can adapt. They spread sodium channels along the bare membrane so that the pulse can travel again, slowly and continuously, as in a fibre that never had myelin. This rescue has a price. Every pulse now lets far more sodium into the axon, which has to be pumped out again at a high energy cost. When energy runs short, sodium builds up, a pump called the sodium-calcium exchanger runs in reverse and calcium floods in, switching on enzymes that break the axon down.[4] This chain, from lost myelin to an energy crisis to a dying axon, is one of the main explanations for why disability can keep growing after inflammation has settled.

Two everyday experiences of MS follow from this physiology. Symptoms that worsen for a while with heat, a hot bath or exercise and then settle again, known as Uhthoff's phenomenon, happen because a small rise in temperature makes conduction in demyelinated fibres fail more easily. And symptoms can recover after a relapse even without new myelin, as axons redistribute their channels and the brain learns to route signals in other ways.

Why axon loss matters most

Lost myelin can be replaced. A lost axon cannot. Pathologists examining brain tissue from people with MS found axons cut through in every lesion they studied, on average more than 11,000 cut axons in each cubic millimetre of an active lesion.[5] Lasting disability is now thought to come mainly from the loss of axons and of the nerve cells they belong to. That is why trials increasingly measure brain volume and neurofilament light, a protein that leaks out of damaged axons into the blood (lesson 7.2).