Understanding Upper Motor Neuron Health - Dr Ozdinler

Back in November Dr Hande Ozdinler gave a presentation to the UK HSP Support Group via Zoom.

Her work has generally been focussed on ALS, which is another type of motor neuron disease, but she brings a useful broad perspective on the health of upper motor neurons. In HSP it is mainly the upper motor neurons which are affected, whereas with SMA (spinal muscular atrophy) it is mainly the lower motor neurons. People with ALS are affected in both upper and lower motor neurons. 

Looking at these conditions which affect the upper motor neurons, we know that those neurons degenerate slowly over time. There are two different areas for that degeneration. Intrinsic issues are those which occur within the neurons themselves, perhaps from a genetic mutation or disruption of messaging. Extrinsic issues occur outside the neuron, perhaps the local environment where the neuron sits is not right.

The majority of the presentation looked at the intrinsic issues. Not only do the upper motor neurons degenerate, there is also degeneration of the connection between the brain and the neuron. This degeneration means that messages cannot pass as easily from the brain to the nerve, preventing or disrupting initiation of movement and the modulation of motor function.

Overall, the degeneration of the neurons accumulates over time, and eventually reaches a point beyond which the neuron cannot function any more. Early detection is useful because it gives the most time to be able to help the cells before they get to the point when they can no longer function.

They have developed a number of mouse models for ALS, and there are similar mouse models available for some types of HSP. The mouse has similar motor neurons as a human, and the functioning of the cells is identical. This makes them good for improving our understanding of the upper motor neurons. Part of the model development has included making the upper motor neurons fluorescent, which allows the cells of interest to be identified more easily, and to look at them in great detail. By looking over time they can see how the neurons degenerate, and see how their behaviour changes over time. 

They also have put forward that upper motor neuron survival should be one of the key indicators for studies, and the fluorescence helps measure this. There are drug discovery pathways to seek out those which can improve the health and integrity of upper motor neurons. 

Some of the proteins involved in upper motor neuron function are secreted into blood, and this offers the potential for a biomarker. Examination of the proteins in the blood should be able to give information on the timing and extent of function loss in the neuron, and identify the underlying cause of the loss.

With understanding of the cause of the loss comes opportunities to begin to formulate treatment strategies. Existing drugs which help that underlying cause in other conditions can be investigated in the case of upper motor neuron degeneration. It is likely that there would be different drugs for different types of upper motor neuron problems, and this is heading towards personalised medicines.

Another aspect they have been working on is using a big data approach to understand the functions affected by the motor neuron degeneration. Essentially by looking at which proteins interact with each other, they can identify a family tree of protein to protein interactions. This moves the focus away from looking at the mutated/absent/over-produced protein and understanding the resulting impacts on those protein to protein activities. The process identifies important functions rather than important proteins, and that opens up different paths in the drug discovery processes and the gene delivery process. They have come a long with with this process on ALS, and they have just started looking into HSP and PLS.

Overall, this was a really useful presentation. There was a lot of technical information given, but my key take-aways are that work done in one condition which affects upper motor neurons easily has potential for help other similar conditions. I was very pleased to hear about the cross-condition work and these new ways of thinking about drug discovery and the specific targeting of medicines.

The image below is a part of a screen shot from the presentation, showing some of the cross-condition work, and of course HSP is grouped into the 'Other' category on the right!