Stem cell research update, March 2012

Here is an update on the stem cell research project from all 5 members of the team – March 2012


Prof. Alan Mackay-Sim

Prof. Alan Mackay-Sim, Co-Principal Investigator


I help chart the direction of the research program, plan and regularly monitor research progress, guide and mentor the research team, analyse and interpret results, and write up the research for publication. I take overall responsibility for the project, funding and publication.


As a neuroscientist and stem cell biologist I contribute to our collaborative team with the overview of how to use patients’ stem cells most effectively to learn how HSP affects human cells, and how potential drugs can correct or compensate for malfunctions caused by HSP.




Prof. Denis Crane

Prof. Denis Crane, Co-Principal Investigator

I contribute my experience in cell biology and biochemistry, and in particular on peroxisomes (one type of microscopic structure inside cells), to the project. Peroxisomal disorders have been the focus of a substantial part of the research I have done over the years. There are a group of neurodegenerative diseases, including HSP, characterised by defective peroxisome transport and distribution in nerve cells.


We have established that there is disruption to the microtubule network within HSP stem cells. One major function of microtubules is to act as the distribution network for moving the different types of microscopic structures (known collectively as organelles) around cells. The project has also shown that certain organelles, namely mitochondria and peroxisomes, have altered distribution with HSP. This is an intriguing finding and is in line with research on other neurological diseases which suggests that disease pathology may be related to altered movement of organelles in nerve cells.


Dr. Yongjun Fan

Dr. Yongjun Fan, Ph.D.

I have been working on the investigation of pathological alterations of HSP stem cells, which we are using as a cell model of HSP.  Some significant cellular and molecular alterations have been identified, and the confirmed data suggest the mechanism of HSP could be different from current thinking. These new findings are being submitted to a high-impact journal for publication. This will be the first report of using human stem cells to investigate the HSP mechanism.

These new findings are more informative because the cells being used are directly derived from people with HSP rather than animals such as mice or fruit flies that have a quite different genetic background.

I will also be performing the drug-screening using this cell model based on the new findings. More than 20,000 compounds may be tested as candidates to cure HSP.



Gautam Wali

Gautam Wali, Ph.D. candidate

In stem cells from people with HSP, differences have been shown between HSP cells and healthy cells. The defect includes difference in distribution of cellular organelles including mitochondria and peroxisomes throughout the cell. The distribution defect is shown to be due to malfunction of the microtubule network of the cell, in which the peroxisomes and mitochondria are transported. This malfunction is hypothesized to be caused by the mutation in the gene SPG 4 that encodes the spastin protein. The defects in distribution lead to degeneration of the corticospinal motor neurons (long nerve cells of the brain and spinal cord) and this is the basic pathology of HSP.


I am working on inducing HSP stem cells to differentiate into neuron-like cells with one long “arm”. The plan is to use these cells to test for potential changes to organelle transport and distribution. I will be working on defining the trafficking defects of the mitochondria and peroxisomes and try to rectify them by screening microtubule specific drugs.



Simon Weyers

Simon Weyers, Ph.D. candidate

I am working on stem cells from HSPers who have mutations other than SPG4. These HSPers show exactly the same clinical features as those with an SPG4 mutation. I am investigating cellular mechanisms that lead to similar or even the same disease patterns, but with different genetic backgrounds.

The first thing is to look at the levels of microtubule severing proteins. It is assumed that alterations in microtubule severing proteins lead to differences in cell organelle trafficking which lead to the onset of HSP symptoms. The proteins of interest in the first set of experiments are Spastin, Stathmin and Atlastin, a binding partner of Spastin that possibly plays a role in the Spastin pathway.

In further experiments we will look at the distribution of cell organelles and start treating the cells with the compounds Vinblastin and Taxol that are known to have an effect on the microtubule scaffold within the cell.
I hope that our research can contribute to a better understanding of this complex disease.


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