As the name suggests, motor neurone disease is a disease in which the neurones that control muscle function, the motor neurones, are dysfunctional and eventually die. This loss of motor neurones from the nervous system gives rise to the outward symptoms of loss of muscle control and wasting. However, motor neurones may not be the only dysfunctional cells that contribute to MND. There are other cells that work closely with neurones within the nervous system that may directly and indirectly affect the viability of motor neurones. Indeed, most of the brain and spinal cord is made up of cells that are not neurones; these cells are known as glia. The word glia comes from the Greek word for glue. Glia are so named due to the belief that the glia was literally held the neurones together. Of the glia, astrocytes are one of the most abundant and may turn out to be one of the most important cell types in motor neurone disease.
What are astrocytes?
Astrocytes are a nonneuronal cell of the nervous system. Astrocytes get their name from their star-like shape (astro means star, as in astronomy). Astrocytes have a number of functions in the brain. Firstly, they can act as scaffolding for neuron movement, including the long axons of motor neurones. They actively participate in the regulation and metabolism of neurotransmitters used by neurones to send signals to other neurones and muscles. In fact, they themselves are thought to be involved in the signaling process. In addition, astrocytes are known to act as scavengers to remove debris from dead or dying neurones.
What is astrocytosis?
Astrocytosis is defined as an increase in the number and size of astrocytes in a specific area of the brain or spinal cord. This is sometimes also referred to as ‘activation' of astrocytes and not only involves changes in their shape and number, but also changes in their ability to clean up debris from dying cells and alters their production of bioactive signaling molecules which they use to communicate with other cells.
Astrocytes respond to spinal fluid of MND patients
It is well known that astrocytosis is associated with all cases (sporadic and familial) of MND. This response of the astrocytes is usually found in the areas of the brain and spinal cord where motor neurones are found. The precise reason for their ‘activation' (see ‘what is astrocytosis' at right) remains a mystery. Some think that this is a direct response to the dying motor neurones. However, research just published, led by Dr Shobha from the National Institute of Mental Health and Neurosciences in India, suggests that astrocytes in the laboratory can be activated by human spinal fluid taken from MND patients. This finding is important because it means that there is an unknown signaling molecule in the nervous system of MND patients that can activate astrocytes. This in turn may have consequences for motor neurone function since active astrocytes can release neurotransmitters, such as glutamate, and other molecules that can be detrimental, such as calcium. If the researchers can find the signal that activates astrocytes it may lead to a potential target for future therapies.
Stimulating astrocytes to clean up glutamate
Much of the brains signaling between neurones is performed by the release and uptake of a substance called glutamate. However, if there is too much glutamate the neurones can be ‘over stimulated' which is bad news for the neurone. This effect is called excitotoxicity. One of the astrocytes' main functions is to clean up the excess glutamate so this does not occur. Picture the game ‘Hungry Hippos'. The balls are the glutamate and the ‘arms' of the astrocytes are represented by the hippos. The astrocytes' job (like the hippos') is to remove the glutamate from the synapse (in our analogy, the game board). In MND patients, uptake of glutamate is thought to be impaired. To compound this deficiency, work coming from Italian researchers found that MND mice have astrocytes that are more likely to release the glutamate that they have cleaned up. The researchers tested the response of astrocytes to a neurotransmitter called GABA. When the cells from MND mice were treated they released more glutamate than cells from mice without MND. Thus, as a whole, regulation of glutamate levels by astrocytes may be impaired in MND patients. With this in mind, a group of researchers from China led by Dr Ran Gu have used adult stem cells taken from adipose (fat) tissue. These stem cells can be manipulated to form a variety of cell types. In this case the researchers used them to form cells that would communicate with astrocytes, stimulating them to clean up glutamate. In the mutant G93A SOD1 MND mice the cells did indeed stimulate glutamate removal. The researchers say these adult stem cells from fat tissue may be a potential treatment for MND.
Source: International MND research update -March 2010, Dr Justin Yerbury for MNDRIA