Features
Chance to Save a Life Motivates Prof
CBS researcher investigates defective protein in rare neurodegenerative disorder that affects children and is ultimately fatal
BY DEIRDRE HEALEY
There's little that is more motivating for researchers than to know their work could one day save lives. That is, unless they have the chance to actually meet the people whose lives they might save.
Prof. Frances Sharom, Molecular and Cellular Biology, can put names and faces to the people she's trying to help with her latest research on Niemann-Pick Type C disease (NP-C), a rare neurodegenerative disorder that affects children and is ultimately fatal.
The renowned cancer researcher has turned her expertise towards unlocking the mystery behind a protein that is defective in NP-C.
“I have met families with children who are suffering from NP-C,” she says, “and that really brings it home when you see the harsh reality of the disease and the impact it has on the people who are affected. This is not some scientific problem - it's real.”
Sharom became involved in this research project just over five years ago when she was contacted by the Ara Parseghian Medical Research Foundation (APMRF), a volunteer organization dedicated to funding research to find a treatment and cure for NP-C and related neurodegenerative disorders.
The foundation is named after Ara Parseghian, former coach of the University of Notre Dame football team, who had three grandchildren die from NP-C. APMRF funds more than 20 research groups across the globe, and each one is focused on a specific area of the disease.
“I am just one piece of the puzzle,” says Sharom. “There are a number of other research projects in progress, covering many aspects of NP-C from molecular biology to animal studies. The foundation is willing to fund relatively risky research and take chances on the fact that it may take years to come up with results. They do this because there really is no other choice.”
About one in every 200,000 children is born with NP-C. Because the disease is so rare, it's difficult to study and it's even more difficult to run clinical trials, she says.
So far researchers have been able to determine that the disease interferes with the body's ability to handle cholesterol. As a result, fatal amounts accumulate in the liver, spleen and brain.
“If the cholesterol is not moved around inside the cell properly, it backs up in a compartment called the late endosomes and causes the cell to malfunction and die,” says Sharom.
This buildup of cholesterol causes the child to lose intellectual function and motor skills and suffer from progressive liver failure and lung complications. Those affected deteriorate so quickly that most don't live past their teenage years.
Researchers are now trying to better understand the function of the NPC protein, which is a large membrane protein involved in normal trafficking of cholesterol inside the cell, in an effort to reveal what the defect is in someone with NP-C.
This is where Sharom comes in. She's studying the NPC1 protein at the molecular level to determine its exact role.
“The work I've done on membrane transport proteins related to cancer is helpful in looking at the involvement of NPC1 in this disease. We know the protein is defective, but no one knows much about what it normally does inside the cell. The APMRF is supporting our research effort because we are one of only a few research groups working on the actual protein at the molecular level.”
To date, she and her team have managed to isolate the protein in amounts large enough for biochemical studies. Using radioactive and fluorescent cholesterol molecules, they have also found that it can bind cholesterol tightly. The extremely low water solubility of cholesterol makes this work very challenging technically, she says.
“The next step is to find out what the NPC1 protein does with the bound cholesterol. We need to search for potential ‘partner proteins' that can accept cholesterol from NPC1.”
By adding fluorescent colour to the protein, Sharom is studying the movement and function of the protein.
“No one knows why this disease happens because no one knows what the protein is doing, and if you want to correct the protein, you need to know what it does. We do know it's clearly an important protein because when it doesn't work, it can be fatal.”
This is tedious and slow-moving research, but Sharom says the project is one of the most gratifying she's ever worked on.
“It's challenging but very exciting. We're doing things that no one else is able to do, and we're making progress. When I think about the parents of these children and how desperate they are for a cure, it definitely pushes me to do the best I can.”