Question: What are the main structural and physiological differences between motor neurons found in healthy individuals and those with motor neuron disease?

Gaby Clarke answered on 5 May 2020:

Hi Mohsin, thanks for your question!

Motor neurons are generally made up of the dendrites, which receive incoming synapses from upstream neurons, the cell body (soma), and the long axon which ends with the neuromuscular junction (NMJ, a specialised synapse between the neuron and the skeletal muscle which signals your limbs to move).

The main structural differences in neurons with MND are the result of degeneration – the dendrites can be shorter and less branched, meaning the neuron will receive fewer signals than a healthy neuron because there are less synapses formed. The cell body may be smaller, and have a smaller, more condensed (stressed) nucleus. The axon leading to the NMJs are often fragmented, and the NMJs themselves are degraded. This all leads to a loss of connectivity within the neuronal circuit, and the neurons are unable to control the muscle anymore, leading to paralysis.

There are many physiological differences that can occur in MND, and these differences may be specific to the gene that is causing the disease (at the moment there are over 50 possible different genes that may mutate to cause MND!). Some of the most common physiological changes include;
-increased neuronal excitability (hyperexcitability) due to increased expression of calcium-permeable receptors on the neuron cell surface
-proteasome impairment, where the machinery that usually makes sure proteins are folded properly, and degrades them if they are not, is not working. This can lead to a stress response called the ‘misfolded protein response’, as well as the build up of toxic protein aggregates and stress granules within the neuron. These stress granules and aggregates can affect normal homeostasis in the neuron by binding to various proteins and RNA, stopping them from getting where they need to be to help the cell function.
-defects in mitochondria, which can lead to reduced ATP generation and therefore low cell energy levels, as well as the production of toxic reactive oxygen species (ROS) which can damage the neuron.

Sorry for the really long answer, but it is a complex question! Let me know if I can explain anything better or if you are interested in hearing more about something specific.