From Bench to Bedside: Parkinson’s Researchers Make Breakthrough Discoveries

From exploring the very smallest of particles, to developing potential new therapies, researchers at Schulich Medicine & Dentistry are looking at Parkinson's disease from perspectives never explored before. In one lab, researchers are spending time on the lab bench, looking at the atomic basis of the disease, and in another, a team is working with patients at the bedside growing large numbers of cells to be used as a potential therapy to treat the disease.

On the Bench
Dr. Gary Shaw, a Canada Research Chair in Structural Neurobiology, and his team in the Biochemistry Department at Schulich Medicine & Dentistry are studying a protein called Parkin that has been shown to play a role in the emergence of early-onset Parkinson's Disease. The protein is found in most cells in the human body, but is found in higher concentration in certain cells in the brain. The protein is made up of 465 amino acids, and just one small mutation in any of those has been shown to be causative for early-onset Parkinson's disease.

Until now, there were regions of the protein that were literal black-boxes; they were shown to have a key role in the onset of disease, but no one had been able to show exactly what they looked like.

"Being able to see a protein on an atomic level allows you to look at that structure and better understand how it really works," says Dr. Shaw. "And in this particular case, because there are these single amino acid substitutions that give rise to the disease, we can also look at the structures and try to identify why those particular regions might be important and why they are so devastating."

Using Nuclear Magnetic Resonance Spectroscopy, the team looked at a portion of the protein called the C-terminal RING2 domain, which had been shown to be important, but had never been studied on the atomic level before. "It was exciting to see the structure for the first time," he says. "And what we saw is that it looked nothing like anyone expected."

What they found was that the C-terminal portion of Parkin actually includes a catalytic triad, which is a combination of any set of three residues that function together and are directly involved in enzyme catalysis. In this case, the triad is made up of cysteine, histidine and glutamic acid residues in a similar fashion to those found in enzymes used in digestion and blood coagulation. Shaw says that the catalytic triad would have been very difficult to identify in the absence of their work on identifying the structure. They also showed that many of the mutations that occur in the protein actually surround this catalytic triad, suggesting that it may be a very key part of the protein with respect to its dysfunction.

Dr. Shaw says the hope is that by understanding the structure, they will be better able to understand the function and the dysfunction of the protein, and therefore better understand triggers for Parkinson's disease.

At the Bedside
Dr. Matthew Hebb, an Assistant Professor in the Departments of Clinical Neurological Sciences, Oncology, and Otolaryngology - Head and Neck Surgery, and his team at the Lawson Health Research Institute have also made a breakthrough discovery related to Parkinson's Disease. They demonstrated for the first time, how small brain biopsies may be used to grow large numbers of cells that could possibly be transplanted back into the patient's own brain. This could prove beneficial in treating various neurological disorders such as Parkinson's disease, but also Alzheimer's disease, Multiple Sclerosis, and injuries of the nervous system such stroke or traumatic brain and spinal cord injuries.

The study enrolled patients with Parkinson's disease who were scheduled to have deep brain stimulation (DBS) surgery. Small biopsies were removed near the surface of the brain and immediately transported to the laboratory while the surgery carried on in standard fashion. These brain cells were multiplied in culture to generate millions of patient-specific cells that were then subject to genetic analysis.

Dr. Hebb says when grown in culture these cells are complex in their make-up but exhibit regeneration, and characteristics of a fundamental class of brain cells called glia. In addition, they express a broad array of natural and potent protective agents called neurotrophic factors, with the ability to preserve and protect brain cells from injury, toxins and diseases.

"With further advances, it's possible that these cells could be transformed in the laboratory to yield specific cell types needed for a particular disease. For example, dopamine neurons in Parkinson's disease or oligodendrocytes in Multiple Sclerosis," says Dr. Hebb.

It may also prove possible to have the cells express specific therapeutic agents such as dopamine or neurotrophic factors that are released directly into the brain when the cells are re-implanted. This drug delivery strategy could play a vital role in exposing appropriate brain regions to continuous and sufficient drug levels, while limiting exposure and possible side effects to the rest of the body.