\ Researchers \ A Fresh Perspective on ALS
Dr. Janice Robertson is not yet a Canadian citizen, but she is already making waves in Canadian ALS research. Robertson began her research in neuromuscular disease with ALS researcher, Professor Nigel Leigh, in London, England. She then travelled to Canada on a fellowship and is now working in McGill’s Department of Biochemistry under Dr. Walter Mushynski.
Robertson’s research focuses on peripherin, a key protein involved in the pathological aggregates found in motor neurons in ALS. One theory about ALS is that mutant proteins have a toxic effect in cells. Robertson seeks information about the proteins that play a role in ALS, with an eye to the overall disease mechanisms. “There currently aren’t enough known gene mutations to account for all cases of ALS,” she says. “It seems likely therefore that other pathways are involved.” Recently, Robertson and her collaborators may have discovered one of those pathways. Their findings, presented in the March 17, 2003, issue of the Journal of Cell Biology, describe how at least one form of toxic protein may arise.
Alternative splicing is a process that allows one gene to generate a variety of proteins. In this way, exons, the coding sequences of DNA, can be extended or shortened, skipped or included, and introns, the non-coding sequences of DNA, can be removed or retained. The proteins generated by this process are called splice variants. Robertson investigated the expression of a protein splice variant called “peripherin” in ALS and discovered that abnormalities in splicing may be an important factor contributing to the disease mechanism.
Peripherin is found in the neuronal aggregates of both ALS patients and SOD-1 transgenic mice. Robertson looked at the behaviour of three splice variants of peripherin. She found that one variant, called Per 61, is particularly toxic. Per 61 did not assemble properly and caused cultured motor neurons to degenerate. “Per 61 kills motor neurons,” says Robertson. “But this actually reveals a mechanism other than just toxic proteins. It also suggests alternative splicing is a potential mechanism involved in the disease.” Robertson believes the alternative splicing mechanism may also produce other proteins that play a role in ALS.
She also has questions about the inflammation reaction, which is implicated in the cascade of motor neuron death in ALS. “I want to find out if there is a connection,” she says. “Does a physiologically compromised motor neuron trigger the inflammatory response, or does the inflammation reaction act on a motor neuron that is not quite as healthy as it should be, thereby killing it? And maybe the inflammation reaction itself leads to alternative splicing and produces toxic proteins such as Per 61.”
Robertson hopes that understanding the role of Per 61 and other splice variants in the overall pathways of ALS will lead to new targets for therapies. With her recent breakthrough in hand and her focus on discovering new clues about ALS mechanisms, Robertson now hopes to become a Canadian citizen and to run her own ALS lab. Let’s hope she gets her way.
Definitions
alternative splicing – a process that allows one gene to generate a variety of proteins.
introns – the non-coding sequences of DNA, which can be removed or retained.
exons – the sequences of DNA that encode for proteins.
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A Fresh Perspective on ALS
Dr. Janice Robertson is not yet a Canadian citizen, but she is already making waves in Canadian ALS research. Robertson began her research in neuromuscular disease with ALS researcher, Professor Nigel Leigh, in London, England. She then travelled to Canada on a fellowship and is now working in McGill’s Department of Biochemistry under Dr. Walter Mushynski. Robertson’s research focuses on peripherin, a key protein involved in the pathological aggregates found in motor neurons in ALS. One theory about ALS is that mutant proteins have a toxic effect in cells. Robertson seeks information about the proteins that play a role in ALS, with an eye to the overall disease mechanisms. “There currently aren’t enough known gene mutations to account for all cases of ALS,” she says. “It seems likely therefore that other pathways are involved.” Recently, Robertson and her collaborators may have discovered one of those pathways. Their findings, presented in the March 17, 2003, issue of the Journal of Cell Biology, describe how at least one form of toxic protein may arise.
Alternative splicing is a process that allows one gene to generate a variety of proteins. In this way, exons, the coding sequences of DNA, can be extended or shortened, skipped or included, and introns, the non-coding sequences of DNA, can be removed or retained. The proteins generated by this process are called splice variants. Robertson investigated the expression of a protein splice variant called “peripherin” in ALS and discovered that abnormalities in splicing may be an important factor contributing to the disease mechanism.
Peripherin is found in the neuronal aggregates of both ALS patients and SOD-1 transgenic mice. Robertson looked at the behaviour of three splice variants of peripherin. She found that one variant, called Per 61, is particularly toxic. Per 61 did not assemble properly and caused cultured motor neurons to degenerate. “Per 61 kills motor neurons,” says Robertson. “But this actually reveals a mechanism other than just toxic proteins. It also suggests alternative splicing is a potential mechanism involved in the disease.” Robertson believes the alternative splicing mechanism may also produce other proteins that play a role in ALS.
She also has questions about the inflammation reaction, which is implicated in the cascade of motor neuron death in ALS. “I want to find out if there is a connection,” she says. “Does a physiologically compromised motor neuron trigger the inflammatory response, or does the inflammation reaction act on a motor neuron that is not quite as healthy as it should be, thereby killing it? And maybe the inflammation reaction itself leads to alternative splicing and produces toxic proteins such as Per 61.”
Robertson hopes that understanding the role of Per 61 and other splice variants in the overall pathways of ALS will lead to new targets for therapies. With her recent breakthrough in hand and her focus on discovering new clues about ALS mechanisms, Robertson now hopes to become a Canadian citizen and to run her own ALS lab. Let’s hope she gets her way.
Definitions
alternative splicing – a process that allows one gene to generate a variety of proteins.
introns – the non-coding sequences of DNA, which can be removed or retained.
exons – the sequences of DNA that encode for proteins.
| Posted On: Monday, April 19, 2004 Modified: Monday, April 19, 2004 Category: Researchers Posted By: |