At the Annual General Meeting of the UK HSP Support Group this past June, Dr Evan Reid gave a historical perspective on HSP research. He initially showed a graph with the number of research articles which cover HSP, ranging between 1947 and now, and described that research into HSP has fallen into three phases.
The first phase – the Clinical Phase, began with the original work of Strumpell and Lorrain, with Strumpell describing the condition initially, and Lorrain fleshing out the detail some more. Another researcher Dr Reid mentioned in this phase was Anita Harding who was working on the clinical definition of HSP until her death in 1995. [Various links with info/obituaries below].
In this Clinical Phase, which ran through till around the 1990’s definitions were made of the:
• different types of HSP – pure and complex,
• features/symptoms of HSP
• pathological anatomy
• inheritance modes
• different complex sub-types.
During the late 1980’s / early 1990’s the next phase started, the Genetic Phase, which ran through until the 2000’s. One researcher noted was Sue (Susan) Kenwrick, who was involved with the first genetic identification of HSP in 1984, which was identified as SPG1. [Various links with info/obituaries below]
In 2007 there was a leap in technology, with Next Generation Sequencing which allowed research to progress at a greater rate and at a cheaper cost than previously, now at about £5,000 per genome. [The first human genome to be sequenced cost $100m, and costs have dropped ever since, roughly following Moores Law until the advent of next generation sequencing, with costs now at $8k per genome http://www.genome.gov/sequencingcosts/].
Dr Reid said that new HSP genes were continuing to be identified, and suggested that overall there might be 100-200 HSP genes in total.
The next area where the sequencing is likely to go is in the investigation of modifier genes. There are some genes which are protective, and others which are enhancing of the action of a gene – i.e. the function of one gene can be helped or hindered by other genes.
In the background, we always have to remember what genes do. The function of a gene is to produce a protein. When a gene is mutated, like various genes are with HSP, then the end result is either that the protein is not produced at all, or there is an abnormality in the production (which may mean too much protein in produced, or not enough, or the protein is not produced properly).
This leads us on to the third phase of HSP research, the Biological and Treatment phase, which began around 2001. To describe this phase Dr Reid gave us a quick lesson in cell biology so we could understand what happens with HSP. This lesson takes the form of an analogy:
• Treat a cell as a company. It is semi-autonomous.
• The nucleus of the cell is the head office, in charge of the company.
• The DNA is the CEO of the company.
• The endoplasmic reticulum (ER) and the golgi apparatus make up the manufacturing department of the company. Proteins are made by the ER and the golgi apparatus packages them up for despatch.
• The plasma membrane, at the edge of the cell is responsible for exporting the proteins that are made.
• There are also receptors on the plasma membrane which undertake market research, identifying if more (or less) proteins need to be made.
• The power for the companies operations comes from the mitochondria.
• Within the cell there are microtubules which are like rails, allowing proteins to be moved from manufacture to export
• There are special motor proteins which are used to move things along the rails.
• The packaging of various things as they move within the cell includes endosomes, which also have a sorting function sorting if things should be disposed of, recycled or sent on.
A neuron is a special type of cell. In addition to the cell described above the neuron also has an axon, which is another method of communicating with the outside world. This is a special part of the cell which can extend away from the nucleus a distance many thousands of times the size of the rest of the cell (up to ~1.5m). Within the axon are microtubules which carry information to/from the nucleus. This arrangement means that the transfer of information between parts of the body is very quick, but complex machinery is needed to support this transfer. The axon from a neuron can connect to the cell of another neuron.
In the majority of types of HSP, the result is degeneration at the end the axon which then progresses. The different types of HSP affect different elements of the axon. Some affect the endoplasmic reticulum (ER), some affect the motor protiens, some the endosomes, and others some of these in combination.
Spastin is a protein which regulates the microtubules within a cell. Its job is to chop them up, which helps to shape or prune them. When you have spastin HSP (SPG4) less spastin is produced, and fewer microtubules are broken up. The essential questions are:
• Why do the microtubules need to break?
• When does a reduction in microtubule breakdown cause HSP?
Perhaps the wrong receptors are on the surface of the cell, so instructions to grow/stop growing/divide/change/etc. are not received properly. This could then influence the cells behaviour. It has been noted that with HSP BMP signalling is unregulated, but it is not known if this is the cause of HSP or an effect of HSP. If it is a cause, then drugs are available for this.
There are three areas where research in HSP is being undertaken to answer these and other HSP questions:
• Cell biology – using microscopes, stem cells, genetic edits
• Animal models – principally mice, zebra fish and fruit flies
• Human studies – HSP clinics
In summary, the genetic identification of HSP is now rapid, which improves diagnosis and allows testing. Within the cell there is an increase in the knowledge of the functions of the proteins. The proteins associated with HSP have inter-related functions. The use of animal models allows quick progression, and stem cell models are also used.
Currently there are several starting points, with potential treatment avenues identified. Thorough research is required to develop treatments.
As an example of how things are progressing, Dr Reid noted Duchenne Muscular Dystrophy. This is a genetic condition which results in muscle degeneration and death by the mid-20’s. Like HSP there is no treatment. However, there has been an overall improvement as a result of the use of combined therapies. In the 1960’s 80% of people with Duchenne MD had died by the age of 20. In the 1970’s this had improved with 60% having died by the age of 20, and with further improvements in the 1980’s and beyond, with some people now living into their 30’s.
For HSP, like the three areas of research there are three areas for treatment. The main area is in rehabilitation, where orthotics or FES may be used, or drugs given to mitigate the symptoms, e.g. baclofen. With genetic testing, advice can be given which provides clarity and frames likely progression. The other area is neurology, where assessments are made in clinic and can guide approaches for treatment.
After the presentation there were a few questions, some of which I’ve built into the text above.
It was asked if spastin could be injected as a treatment. For this to work you’d have to inject it directly into the neuron, which would be difficult to do. It is also very difficult to get spastin isolated by itself.
Stem cell research was touched on briefly, noting that it could be possible in the future to edit the DNA to remove the spastin mutation from stem cells and then re-inject them, but the issue is getting the these to the neurons. Dr Reid noted that at the moment about 10% of stem cell injections resulted in a tumour, but this may be useful in the future.
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