This post describes the information given to the UK HSP Support Group at one of their AGM presentations via Zoom in 2022.
The presentation was given by Prof Andrew Crosby and Dr Emma Baple from Exeter University. They gave an overview of the work that their team has been doing in recent years. The HSP support group had part-funded Olivia Rickman for her PhD studies, and this presentation was to report to members the outcomes of the research that we had funded. You can watch the full presentation here: https://www.youtube.com/watch?v=Mfk6qap2ric
Commonalities
They began by describing that their work covers more than just HSP, and that there is learning from different motor neuron disorders that helps improve the understanding of HSP, and similarly the work on HSP often helps understanding of other motor neuron disorders. Several of these motor neuron disorders (including HSP) affect the upper motor neurons, and there are a range of similarities in these conditions.
HSP genes
Their work has been looking at genes, with the human having some 22-25,000 genes, of which about 7,000 are understood. Genes code life, and their job is to make proteins, which then go on to build up life. Their team have discovered 16 genes which are responsible for HSP so far. Once identified these genes offer the potential for genetic testing for families and can give insights into how HSP works. HSP changes the genetic coding of the gene, which then affects how the protein is made. Their work then seeks to understand how the HSP affects the proteins, the role of the protein within the cell, and how the change made by HSP affects that role. With this they can find out what the motor neuron is supposed to be doing, and why it is not doing that with the HSP, which offer the potential to investigate options to intervene.
Genetic Testing
In England the genomic medicine service was recently launched, which allows whole genome sequencing. This sequencing takes a matter of days to give the whole genetic sequence. There are two panels of genes that are tested against for HSP, there is a panel with 76 genes currently for adults and 70 genes currently for children. Some genetic conditions have genetic overlap with multiple conditions, and there is a broader panel of neurodegenerative conditions which can be used, which tests against 96 genes, some of which are HSP genes.
Despite knowing about all of the HSP genes discovered so far, a genetic diagnosis of HSP can only be given to about half of people, which indicates that there are still a lot more HSP genes to be discovered. It is understood that the majority of the more common genes for HSP have been identified, which means that those genes which have not yet been identified will each affect a relatively small number of people.
Commonalities between HSP types
One of the key questions is why are there so many different genes which cause HSP - in more detail do these genes all have unrelated functions or roles or do these genes work together in common pathways within the cell. It is thought that the common pathways are more likely, so that any of the HSP genes can affect one of the common pathways, giving rise to HSP. Essentially the symptoms of HSP arise because of a problem in the common pathway. The main issue with these studies is that the function of many of the genes understood to cause HSP are not known or not well known, so identifying the common pathway is difficult.
Two of the HSP genes discovered by the team are in pathways which are well understood, so this gives a good link between HSP and these pathways, and allows understanding of HSP on the pathways to be explored. One of these is CYP7B1 on the cholesterol pathway and the other is EPT1 on the kennedy pathway. Both pathways are to do with processing fats and cholesterols, which show that these fats and cholesterols are important for HSP.
The team then looked at the other genes which have been associated with HSP to examine if these are associated with those pathways. There is some evidence which links some of these genes to these pathways. One of their recently identified HSP genes (TMEM63C) was also found to be at a key location for the fat processing routine.
Future work
When looking at the plans for future studies they are focussing on two areas. One area is to continue to find more HSP genes to understand more about the pathways and how they are affected with HSP. The other area is to look at the fat processing pathways and to understand what happens when the pathway is disrupted by HSP. Whilst these pathways are understood to some degree, the differences between how they work within different cell types is not so well knows. This area is challenging and new processes have been developed for the analysis work. They have been creating cell models for HSP and editing the genes to take the gene out. This then allows the cell to work in a similar way to how they would work in a person, and this then allows the cell functions and associated impairments to be studied.
The team are using this technique to be able to compare different types of HSP to be able to examine similarities and differences in the fat processing pathways to be able to confirm which HSP genes are involved in these common pathways.