Progress report from the researchers
Principal Researcher, Prof. Alan Mackay-Sim
Some dreams do come true. When I was first approached by inaugural Foundation President, Robin Bligh, to start research on HSP, we had dreams that we could use olfactory (nasal) stem cells to find out what goes wrong in HSPers that leads to the disease, and then to seek chemicals that might be future drugs. Five years later we know many things that go wrong and we are on the track to find drugs. We are excited to see what the cells will tell us in the next 6 months. Our progress will be accelerated by two new team members visiting the lab for the next 3 months.
Dorothee Mugele, from Dresden, Germany, is a Masters student on an internship funded by her university who will be working under Simon’s supervision on his tubulin dynamics experiments.
Johanna Fernandes is a third year undergraduate student in Biomedical Science at Griffith University. Johanna is working under Gautam’s supervision investigating movement of other cell organelles.
In our recent publication we demonstrated two major new insights into what happens in cells from people with spastin mutations. These were a reduction in stable microtubules and slowing down of peroxisome movements. Microtubules are made of tubulin and over the last quarter I have been testing drugs that bind tubulin to find whether we can reverse the impairments in microtubules and peroxisome movements in HSP stem cells. I tested different drug doses to find some that are effective at very low doses. I am now drafting the paper that will be submitted soon to an international journal.
An important next step is to see if the impairments we see in the HSP stem cells are also seen when those cells develop into neurons (nerve cells). In the last three months I have found a chemical treatment that encourages the stem cells to turn into neuron-like cells which are being used by Gautam and Simon in their investigations. I am now developing this process further to make genuine neurons.
Part of my job is to help supervise the work of everyone in the lab.
I have been studying the movement of peroxisomes in HSP stem cells. Peroxisomes are “organelles”, tiny bodies important to energy metabolism that must be moved around for normal cell functioning.
To study their movement, the peroxisomes are “labelled” with a fluorescent marker (see photo) and photographed using time-lapse images. A computer program then finds each peroxisome and tracks its movement.
The first experiment showed that peroxisome movement in HSP cells is impaired. They move slower than in normal cells. In the second experiment, HSP stem cells were modified into “neuron-like” cells so that they would be structurally more like the nerve cells that are impaired in people with HSP. Neurons are nerve cells with one long arm or axon. Even more impairment of peroxisome movement was observed in these cells. This experiment also provided us with some insight as to why only nerve cells are affected in HSP.
In the third experiment, four potential drug compounds were tested and it was found that all could rescue the impaired peroxisome movement.
Continuing investigations of microtubule dynamics have occupied the last three months. Microtubules are the ‘highways’ that transport peroxisomes around cells. However they are not stable and keep getting built and taken down in the cell. Microtubule dynamics in HSP cells have been shown to be different from those in normal cells.
At the end of May I presented my most recent work in a poster presentation at a postgraduate student conference held by the Australian Society for Medical Research. In July I went to Sydney to visit the lab of our collaborator Prof. Carolyn Sue from the Kolling Institute of Medical Research.
As a result of that visit we are now establishing stem cells from HSPers carrying a mutation in the SPG7 gene. This will help us understand what cell impairments are common to people with different HSP mutations. We are hoping to be able to better reflect the diverse genetic background of the disease by adding more cell lines to the stem cell bank.