Vancouver research team plays key role in discovering the most common cause of ALS and Frontotemporal Dementia

Dr. Ian Mackenzie, neuropathologist at Vancouver General Hospital and professor in the Department of Pathology and Laboratory Medicine at UBC is part of a North American team of researchers who found a genetic abnormality they believe to be the cause of two major neurodegenerative diseases: FTD (frontotemporal dementia) and ALS (amyotrophic lateral sclerosis).

Led by neurogeneticist Rosa Rademakers at the Mayo Clinic in Florida the researchers found a short DNA sequence repeated hundreds to thousands of times in almost 12 percent of familial FTD and more than 22 percent of familial ALS of samples studied.

Their findings are published in the September 21 online issue of Neuron.

“This is the most common genetic defect, in both familial and sporadic cases, identified to date in these two different, but equally devastating neurodegenerative conditions, and confirms an overlap between FTD and ALS at the molecular level,” says Dr. Mackenzie.

The abnormally expanded repeat of C and G (two of the four nucleotides that make up the genetic code) was found in a gene on chromosome 9 called C9ORF72, which encodes a protein whose normal function and role in disease are currently unknown.  However, the researchers found evidence that when the defective gene is transcribed into a messenger RNA molecule, the expanded repeat section accumulates in cells and binds tightly to other critical proteins, thus preventing them from carrying out their normal cellular functions.

Dr. Ian Mackenzie’s research team at the Brain Research Centre was instrumental in this discovery. In addition to providing invaluable genetic samples from a number of well-characterized BC families with FTD and ALS, Dr. Mackenzie identified a pattern of pathology in the post mortem brain tissue of patients that accurately predicted the presence of the mutation. As a result, the collection of cases provided by Vancouver researchers had the highest frequency of the mutation (62%) of all series studied. In addition, Dr. Mackenzie played a key role in defining the impact of the mutation on brain cells by demonstrating abnormal patterns of protein expression and the presence of the potentially toxic accumulations of mutant RNA.

“The data we obtained from our UBC Hospital families was instrumental to this study,” Mackenzie says. “It provided us crucial understanding of the mechanism of brain injury and potential avenues for therapeutic intervention.”

In the short term, this finding will aid in the genetic counseling process for affected families and in the longer term, is crucial for the development of new treatments.

After Alzheimer’s disease, FTD is the second most common form of early onset neurodegenerative dementia. It is characterized by changes in personality, behavior and language due to loss of gray matter in the brain’s frontal and temporal lobes. ALS destroys motor neuron cells that control essential muscle activity such as speaking, walking, breathing and swallowing.

Researchers have recently found similarity between the two disorders: Up to half of ALS patients experience symptoms of FTD, and, similarly, up to half of FTD patients develop clinical symptoms of motor neuron dysfunction seen in ALS. Both diseases can also occur in the same family and post mortem examination often shows abnormal accumulation of the same proteins in the brain.

This is one of several successful collaborations between Dr. Mackenzie’s VCH and UBC team and the Mayo Clinic around the causes of FTD. In 2006, they discovered mutations in a different gene (called progranulin) to be another important cause of familial FTD. That work was published in the prestigious journal Nature and the American Journal of Human Genetics.

The VCH and UBC FTD research program is supported by funding from the Canadian Institutes of Health Research and the Pacific Alzheimer’s Research Foundation.