Disease Processes in MND: Part 2

Following on from last year’s blog where you would have read about the disease processes – disturbances in protein quality control, from the review paper “Decoding ALS: from genes to mechanism”, this week we are going to focus on topics b, c and d as these highlight the impact of other cell types, not motor neurons, in MND.

Figure 1. Mechanisms of disease implicated in MND (adapted from Taylor JP et al., 2016)

Firstly, here is quick explanation of the structure of a motor neuron as this will be helpful in explaining ways in which other surrounding cells contribute to disease.  

Figure 2. Structure of a motor neuron.

Soma (cell body) – the part of the motor neuron found in the brain or spinal cord

Dendrites – the branches of the cell that connect with other neighbouring neurons so that they can send signals between cells

Nucleus – found in every cell and contains all the genetic material (DNA)

Axon – the long branch (can be up to 1 metre long) of the motor neuron that stretches from the cell body to the terminal (muscle end)

Myelin sheath – a coating around and along the axon created by myelin-producing cells (either oligodendrocytes or Schwann cells) wrapping around the axon. This aids in the delivery of electrical messages along the axon.

Axon terminal – the part of the motor neuron that connects with the muscle and controls movement

(Image obtained from http://ib.bioninja.com.au/standard-level/topic-6-human-physiology/65-neurons-and-synapses/neurons.html

 

Glial cells and the central nervous system (CNS) immune response

Motor neurons are not alone in the brain and spinal cord. They are supported by blood vessels, immune cells and a number of different types of support cells termed “glial” cells. Although MND selectively kills the motor neurons, researchers have discovered that other cell types are also involved in the advancement of disease.

Glia  comes from the Greek word meaning “glue”, as glia were thought to simply be scaffolds that provided structural support for neurons and held the brain together. We now know as well as providing strong structural support, particularly for the transport of proteins and signals along the axon, glia have other vital roles including providing growth factors, energy and nutrients, removing toxic chemicals and waste products and removing pathogens and dying cells. Unlike neurons which are post-mitotic (meaning they cannot undergo cell division) glial cells are reactive and increase in number and size in response to pathogens or injury. This process, termed “reactive gliosis”, is seen in the early stages of MND progression, with increased numbers of large glial cells observed surrounding motor neurons.

In the central nervous system (CNS) there are 3 different types of glial cells. These are the astrocytes, oligodendrocytes and the microglia. The structure of these glial cells varies, particularly in size, but all have a similar star-like shape with a small cell body and many complex branches. Glial cells wrap their branches around neighbouring blood vessels, other glial cells and neurons, allowing these cells to interact and pass nutrients and signals between each other. The interconnected environment that neurons and glia exist in can be seen in the picture below and in this video of some 3D imaging in the brain.

 

Figure 3. Glial and neuronal networks in the brain and spinal cord

Topic b. Hyperactivation of microglia

Microglia, as their name suggests, are the smallest glial cells, but their role as the immune cells of the CNS is very important. Microglia exist in a resting inactivated state, where they survey the CNS for any cellular stress, injury or pathogens. In response to a small or short-term injury, microglia will become activated, increasing their size and numbers and flocking to the injury site where they attempt to restore the tissue and reverse the cellular stress. In these circumstances, microglia are very beneficial to motor neurons. However, when cells undergo a chronic or irreversible stress (such as during MND), microglia switch from an anti-inflammatory cell to pro-inflammatory where they release toxic factors that contribute to the death of motor neurons. In animal models of MND or in post-mortem tissues from MND patients, hyperactivated microglia of the pro-inflammatory type can be observed throughout the brain and spinal cord, but are primarily localized near degenerating motor neurons.

Topic c. Diminished energy supply from reduction in MCT1 transporter.

Oligodendrocytes (or oligos) are cells that produce a fatty tissue called “myelin” which wraps around the axon of neurons to improve the speed and quality of the electrical signal between the brain and spinal cord and the muscles. Another key function of oligos is to supply motor neurons with energy (in the form of lactate), through a specialised transporter called the monocarboxylate transporter 1 (MCT1). A loss of myelin (termed demyelination) caused by injury to oligos occurs early on in disease in MND patients and MND animal models. Also, levels of MCT1 are reduced which results in a decreased energy supply to neurons.  Hence, oligo injury results in impaired signalling along motor neurons and decreased energy supply, both of which contribute to MND progression.

Topic d. Excitotoxicity from reduced glutamate uptake.

Like microglia, astrocytes have important immune role in the CNS and will flock to an injury site (e.g. following stroke, spinal cord injury, MND) and increase their size and expression of a key astrocyte protein called GFAP. Activation of astrocytes is another common hallmark of MND and like microglia, these enlarged cells expressing high levels of GFAP are usually observed in areas where motor neuron loss has occurred. Astrocytes have another key function which is heavily associated with MND – the uptake of the chemical glutamate.

Glutamate is the main chemical messenger in the CNS that neurons use to send signals to each other. Neurons will release glutamate from inside their cell into the space between cells (extracellular space), where it will act to excite the neighbouring cell. The neighbouring neuron will then release glutamate and excite its neighbouring cell and so on and so on. While glutamate is vital for signalling, excessive amounts of it in the extracellular space can be toxic as it will continue to keep exciting the neurons around it and repeated activation of neurons, termed excitotoxicity, is harmful. Astrocytes, which from the 3D video you can see surround neurons, remove glutamate from the extracellular space and take it up into the cell via a glutamate transporter (GLT-1). Astrocytes convert glutamate to glutamine which is a non-toxic form of glutamate. In MND, levels of GLT-1 are reduced which leads to a build-up of glutamate in the extracellular space, over activation of neurons and excitotoxic injury to neurons. The drug Riluzole, which is currently used to treat MND, acts on this pathway to block the over activation of neurons and reduce excitotoxicity.

Glial cells as targets for MND therapies

Hopefully this blog has shown how cells other than motor neurons can contribute to MND. A number of studies in MND models have shown that manipulating glial cells to switch from their activated, pro-inflammatory state to an anti-inflammatory, protective state is beneficial and can increase survival time. Thus, drugs that target glial cells are now being tested in MND clinical trials and may show that improving the health of your glial cells will slow the loss of motor neurons.