ALS Research Team at the Tanz Centre and Dr. McGoldrick

The ALS team at the Tanz Centre started in 2004 under the leadership of Dr. Janice Robertson.   A world renowned ALS researcher, Dr. Robertson has assembled the leading minds in ALS research in an open and collaborative environment.  As the head of one of the largest ALS Labs in Canada, Dr. Robertson was the recipient of a Premiers Research Excellence Award and a Canada Research Chair in ALS. 

In close collaboration with Dr. Lorne Zinman, head of the largest ALS clinic in Canada, and Dr. Ekaterina Rogaeva, a geneticist at the Tanz Centre, Dr. Robertson has established the only comprehensive clinical database, blood and tissue sample collection in Canada. This is a critical achievement and indispensable to research and has formed the basis of numerous important global collaborations.

The work of Dr. Robertson and other ALS researchers in her team are published in high impact international journals. The team of scientists is regularly invited to give talks at international meetings and sit on international grant review panels as well as international workshops aimed at drug development.

Dr. Robertson takes this spirit of collaboration globally, forging partnerships with other leading ALS researchers in Japan, China, US, France and the UK. 

Dr. Philip McGoldrick is a rising young star of ALS research. He obtained a first class honors B.Sc. in Neuroscience and his Ph.D. in the study of ALS from the Institute of Neurology, Queen’s Square London UK. Dr. McGoldrick chose

Dr. Robertson’s laboratory as one of the best in the world to advance his career and he was successful in obtaining a prestigious and highly competitive Milton Safenowitz Postdoctoral Fellowship from the American ALS Association.

Dr. McGoldrick could choose any laboratory in the World, and to retain his talent at the Tanz Centre is critically dependent on philanthropic support. 

Dr. Philip McGoldrick's Published Research (2018)

Description of McGoldrick et al., 2018, Neurology

“Unaffected mosaic C9orf72 case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression.”

 

Although ALS mostly occurs randomly and we don’t know why, around 10% of cases run in families due to a harmful change (mutation) in DNA (your genetic blueprint), and these are termed inherited, familial or genetic cases. Crucially, in the clinic and down a microscope, random and inherited cases look identical – meaning that study of the inherited cases, where we know the exact cause, could hopefully benefit random cases too.

 

The most well known cause of inherited ALS cases is because of an unusual mutant DNA in a gene called C9orf72. Instead of this piece of DNA being 2-30 pieces in length (Diagram 1), in some families it has expanded to over 1000 pieces long (Diagram 2).

 

 

 

 

 

 

We don’t know why or how this piece of DNA gets so big, or why it then causes ALS – but it has been suggested that it could be a combination of making too many toxic products (RNA foci, dipeptide repeat proteins), and/or not enough normal products (Part 2).

 

 

 

 

 

 

 

 

 

There are also two intriguing other facts: firstly, there are very few reports of intermediate (above 30, but less than hundreds/thousands) lengths, and secondly, some random cases have also been found to have an abnormally large piece of DNA, and we can’t explain why.

We studied a family in which a parent without ALS had an intermediate length of the DNA (70 pieces long), but their children had over 1000 and developed ALS. As part of a collaborative effort from investigators at the Tanz CRND (University of Toronto), Sunnybrook Hospital and the Mayo Clinic Jacksonville (Florida), we carried out an investigation find out why the parent didn’t develop ALS, and what the properties of an intermediate length of DNA are.

 

In the parent, we found that the intermediate length of DNA was actually very unstable in their brain and spinal cord (the areas of the body that degenerate in ALS), and was a mixture of lengths ranging from 70 up to sizes that cause disease (which we describe as mosaic) (Diagram 3).

 

 

 

 

 

Having the large piece of DNA (over 1000), usually reduces the amount of normal products that are made from this blueprint, but unexpectedly we because the parent had some intermediate lengths of DNA, this actually increased its products.

 

We next used a microscope to take a closer look at the brain and spinal cords of the parent and their offspring - to assess them for toxic products of the large DNA and any hallmarks of ALS. Intriguingly there were as many signs of toxic products from the large DNA in the parent as there were in their offspring, but the parent did not show any hallmarks of ALS.

 

We’ve shown that in the parent, who never developed ALS, their intermediate length (70) of DNA is unstable and created a mixture of lengths from 70 to over 1000, and unusually this mixture of different lengths caused the normal products of DNA to be increased. Despite having some large sizes of DNA and a lot of their toxic products, the parent never developed ALS. We think that this is important for 2 main reasons: 1) increased amounts of products from the intermediate DNA may be protective against the toxic products from the long DNA (Part 3), and 2) some apparently random cases that have the large DNA may not be random at all – their parents may be similar to the parent of this family.

If you are interested in learning more, you can find Dr. McGoldrick’s publication here.

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