\ Researchers \ Fellowship continues to keep Tim E. Noël's spirit alive
To honor Noël, the ALS Society of Canada established the Tim E. Noël Fellowship in ALS Research in 2006. This is a partnership between the ALS Society of Canada and the Canadian Institutes of Health Research’s Institute of Neurosciences, Mental Health and Addiction, which recognizes and supports post-doctoral ALS researchers by awarding each recipient up to $55,000 annually for a maximum of three years.
Untangling the mystery of disorganized filaments
Rodolphe Perrot, PhD, is the Tim E. Noël Fellowship’s 2008 recipient. With the guidance of Jean-Pierre Julien, PhD, Canada Research Chair in the Mechanisms of Neurodegeneration and Professor of Anatomy and Physiology at the Centre Hospitalier de l'Université Laval (CHUL) Research Centre, Québec, Perrot is working on his project titled “The study of pathogenic mechanisms associated with the disorganization of neuronal cytoskeleton.”
The neuronal cytoskeleton is an interior scaffold that helps to maintain the shape of neurons. It is composed of three interconnected parts: actin microfilaments, microtubules and intermediate filaments. Accumulations of disorganized intermediate filaments are the hallmark of many neurodegenerative disorders including ALS and Parkinson’s disease. However, why or how the intermediate filaments become disorganized is unknown.
Perrot received his doctoral degree from University of Angers, France, where his research focus was neurofilaments, a family of intermediate filaments. “During my doctoral studies, I analyzed the function of neurofilaments in normal conditions,” says Perrot. “I now wish to focus my studies on disease-associated aspects of the neuronal cytoskeleton.” He shifted his research focus to ALS because he felt that the disease deserved more attention. Building on his knowledge of the neuronal cytoskeleton, Perrot hypothesizes that abnormal intermediate filaments can influence fast axonal transport, an important process by which the neuron transports molecules along its axon.
Using mouse models that display various intermediate filament abnormalities, Perrot will capture time-lapsed images of axonal transport of mitochondria and lysosomes. The two organelles are chosen for their critical functions in the neuron: mitochondria generate energy for cellular activities and regulate calcium concentration, whereas lysosomes degrade cellular waste. Perrot will collaborate with Jasna Kriz, MD, PhD, Assistant Professor at the CHUL Research Centre. “They have a new, non-invasive imagery system that enables the measurement of bioluminescence intensity in vivo. Thus we could analyze axonal transport directly in our models,” Perrot explains.
Cytoskeleton proteins play multiple roles in neurons, such as providing structural organization for the cell interior and assisting with transporting materials within the cell. Perrot will therefore also analyze the expression and distribution of cytoskeleton proteins in a different set of mouse models, and try to understand how they affect axonal transport.
With growing evidence that intermediate filament accumulations are directly involved in causing ALS symptoms, researchers are working hard to better understand the cascade of cellular events leading to the disease. Perrot believes that insight into cytoskeleton abnormalities may one day allow the design of targeted pharmacological interventions for both inherited and sporadic forms of ALS.
Calcium toxicity: another clue in SOD1 motor neuron death
Other recipients of the Tim E. Noël Fellowship are making great strides with their research. Sherif Elbasiouny, PhD, at Northwestern University, Illinois, received the award in 2007. His two-part research is titled “Ionic mechanisms underlying motoneuron degeneration in ALS.”
In his first project, which is now complete, Elbasiouny used computer simulations to investigate changes in the physical and electrical properties of motor neurons (also called motoneurons) expressing mutant superoxide dismutase-1 (SOD1), the only confirmed cause of an inherited form of ALS. The study was inspired by recent reports of mutant SOD1 motor neurons that became enlarged and developed complex dendritic structure shortly after birth, but long before the onset of ALS symptoms in transgenic mice. “Learning more about these early alterations in motor neuron properties before their degeneration is critical to understanding ALS pathogenesis,” says Elbasiouny.
Indeed, he found that changes in the size and shape of mutant SOD1 motor neurons accounted for changes in their electrical properties. But this was not the whole story. Elbasiouny also observed a large amount of calcium ions rushing into the mutant motor neuron as it generated electrical impulses. This resulted in a much greater concentration of calcium than in normal motor neurons, which quickly led to calcium toxicity and cell death.
This project was a great success, with results presented at ALS Canada’s 4th Research Forum, held in Toronto, and the “Mechanisms of Plasticity and Disease in Motoneurons” conference in Seattle. A research paper on this study is expected to be completed by the end of 2008.
Influence of drugs and neuromodulators on motor neuron
Elbasiouny is now working on his second project under the guidance of Charles Heckman, PhD, Professor of Physiology at Northwestern University. He has developed an in vitro sacral cord preparation to directly measure electrical properties of motor neurons in the presence of various drugs including Riluzole, the drug currently used to treat ALS.
Elbasiouny will also examine the effect of two neuromodulators -- serotonin and norepinephrine. Neuromodulators are chemical substances released in the brain and spinal cord to modulate the excitability and firing activity of neurons. Since excitability is a feature closely related to degeneration of mutant SOD1 motor neurons, the relationship between neuromodulators and motor neuron survival is worth examining.
Elbasiouny hopes to identify the exact electrical stimulation and pharmacological approaches that can modulate electrical properties of motor neurons. “My main motivation and research interest is to help individuals with disabilities or neurological diseases,” says Elbasiouny, who hopes to set up his own ALS research lab after the post-doctoral training. “The pharmacological results could suggest new drugs to be tested in human clinical trials.”
Antibodies may lead to effective vaccination and diagnostic tool
The first Tim E. Noël Fellowships were awarded to François Gros-Louis, Edor Kabashi and Joe Chakkalakal in 2006. All of them report tremendous progress in their research.
The project of François Gros-Louis, PhD, is titled “Identification of misfolded proteins associated with sporadic ALS through innovative proteomics approaches.” He reached an important milestone when he was part of a research group that successfully synthesized antibodies to recognize misfolded human SOD1 proteins in transgenic mice. “The antibody is a valuable tool for studying proteins,” he explains from the lab of Jean-Pierre Julien at the CHUL Research Centre. “Since we are directly looking for misfolded proteins instead of gene defects, we call this a proteomic-based approach.”
Using the same antibodies, Gros-Louis also identified misfolded SOD1 proteins in the spinal cord tissues of people who died of familial (inherited) or sporadic ALS. This was surprising, since the antibodies managed to detect misfolded SOD1 proteins even though they were targeted to the mutated forms only. Based on preliminary results, Gros-Louis now thinks that misfolded SOD1 proteins exist in some cases of sporadic ALS.
At the same time, other members of the Julien research group showed that misfolded SOD1 proteins could be secreted outside motor neurons. They also demonstrated that post-translational modifications such as oxidation could give normal SOD1 proteins toxic properties similar to those observed in the mutant forms.
The success of Gros-Louis’s research has led to several new developments including an antibody vaccination for SOD1 mutation-linked ALS. “Chromogranins (molecules secreted by nerve cells) engage in specific interactions with different mutant forms of SOD1. Based on this observation, we have proposed a new ALS disease model and tested active immunization protocols that successfully delayed disease onset and increased survival in an ALS mouse model,” Gros-Louis explains.
“However, passive immunization may be safer since administration of antibodies may be stopped at any time if the recipient shows adverse symptoms during treatment,” he adds. “In the passive approach, antibodies are transferred or infused into the person with ALS. This is contrasted to active immunization, where we help the immune system generate its own antibodies. We’ve tested the passive approach in mice and found that our antibodies were also effective in delaying disease onset and increasing survival. More tests need to be done before we can develop immunotherapy for humans, but this is really exciting news.”
As the next step, Gros-Louis will try to identify misfolded SOD1 proteins in blood or cerebrospinal fluid – samples readily available from people living with ALS. “It is imperative to fully characterize the antibodies we have developed,” he says. “These antibodies were generated in mice, so we need to ‘humanize’ them to avoid drastic and lethal immunological effects.”
In addition to treatments, the new antibodies may eventually form the basis of new diagnostic tools for detecting ALS at the early stages or monitoring disease progression. For now, the antibodies are giving researchers like Gros-Louis a better picture of ALS caused by mutant or misfolded SOD1 proteins. “We now have in our hands the tools to understand the pathogenic mechanism,” he says.
New gene mutation gives insight into neuron death
Edor Kabashi, PhD, is attempting to understand ALS from different perspectives. A post-doctoral fellow of Guy Rouleau, MD, PhD, Professor of Medicine at the Université de Montréal, Kabashi has thus far contributed to studies that were published in high-impact journals such as Nature Genetics, Annals of Neurology, Human Molecular Genetics and Journal of Neurochemistry.
In his project, “Developing and characterizing novel models of ALS and other neurological disorders in zebrafish,” Kabashi developed two animal models to investigate the function of a protein called alsin, which is encoded by the Als2 gene. Mutations of Als2 are associated with juvenile ALS, a rare form of the disease. The Als2 gene was “knocked out” or engineered to be non-functional in the mouse model, whereas in the zebrafish model, the gene was only “knocked down” and showed limited expression. By comparing the levels of neurodegeneration in the two models, Kabashi and colleagues identified a variation of mRNA (messenger RNA which contains protein-encoding information) that seemed to prevent and regulate severe neurodegeneration symptoms.
During his doctoral studies, Kabashi worked with Heather Durham, PhD, Professor at McGill University, Montreal, to examine the role of proteasomes in SOD1 mutation-linked inherited ALS. Proteasomes are protein complexes that belong to cellular pathways responsible for handling misfolded, damaged or mutant proteins. In analyzing the mechanisms of proteasomes in ALS mouse models, Kabashi found that structural changes were the main reason for the proteasome’s reduced ability to break down unwanted proteins.
One of Kabashi’s greatest successes as a post-doctoral fellow has been his role as the co-investigator in the discovery of TDP-43 gene mutations in both sporadic and inherited ALS. Although the protein product of TDP-43 is still not well understood by scientists, it is a major component of protein inclusions, or clumps of proteins, in the brains of people with ALS and frontotemporal dementia (FTD). Working with PhD candidate Paul Valdmanis and other Canadian and French researchers to screen the genes of 200 ALS patients, Kabashi identified eight distinct mutations in nine individuals with sporadic or inherited ALS. The new report of TDP-43 gene mutations provides additional evidence for the role of this protein in causing motor neurons to degenerate.
With this discovery, Kabashi plans to study the functional role of TDP-43 in diseased cellular and animal models. “Training with Dr. Guy Rouleau has given me a better understanding of ALS as a clinical disease,” he says. “In my previous research, I worked mainly with animal and cellular models of ALS. During the last two years, I’ve had the chance to meet people with ALS and their families, which gave me a perspective of what a difficult disease ALS is. This certainly inspires me to continue with my research.”
Understanding the connection between neurons and muscles
Joe Chakkalakal, PhD, is a post-doctoral fellow of Joshua Sanes, PhD, Professor of Molecular and Cellular Biology at Harvard University in Boston, Massachusetts. His project is called “The establishment of motor unit homogeneity during development and after axon regeneration.” Using imaging technology and transgenic ALS mouse models, Chakkalakal hopes to better understand how motor neurons and muscle fibres communicate during normal development and after injury. Together, a motor neuron and the muscle fibres that it innervates form the motor unit.
“I have characterized two BAC transgenic fluorescent reporter mouse models to track the development and patterning of muscle fibres,” says Chakkalakal of his major success thus far. BAC stands for bacterial artificial chromosome, a molecular technique that allows the direct study of gene expression in animal disease models. BAC contains the gene of interest and a reporter gene that acts as an easily identifiable and measurable marker. The reporter gene in Chakkalakal’s mouse models produces fluorescent proteins that glow under specific lighting.
The slow motor neuron is a type of neuron that releases small amounts of neurotransmitters to generate small contractions in muscle fibres. As the signal-carrying neurotransmitters accumulate, the muscle contractions gradually become more intense. “It seems that particular types of motor units, such as the slow type, are relatively resistant to pathological consequences of ALS,” explains Chakkalakal. “It’s therefore important to understand how slow motor units develop and what makes them resist disease progression.”
Chakkalakal decided to give the slow motor unit a closer look and studied the synaptic vesicle protein 2 (SV2), which is secreted by neurons into the point of connection between motor neuron and muscle fibre. He soon isolated a specific form of SV2 that was selectively expressed in slow motor neurons. Analyzing slow motor units during development and after injury is difficult due to the lack of techniques to do so, but this challenge may soon be overcome with Chakkalakal’s discovery of the specific SV2. “This may help identify potential therapeutic targets and perhaps prevent disease progression of ALS,” he says.
“We now have a model system to help us come up with strategies to observe how neurons develop, respond to insult and behave in neurodegenerative disorders,” continues Chakkalakal, whose direction in ALS research stems from his interest in the development of motor units. “Some of the remaining challenges include using transgenic mouse models to understand the behaviour of particular types of motor neurons and motor units in response to damage or disease.”
In the coming years, the Tim E. Noël Fellowship will continue to leverage funds and encourage young scientists to pursue ALS research. With the award recipients’ passion and commitment to ALS research, our knowledge of ALS is significantly advancing.
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Fellowship continues to keep Tim E. Noël's spirit alive
Tim E. Noël’s philosophy of life was simple: “Today is a gift. That's why they call it the present. And you should never let the thieves of yesterday or tomorrow rob you of that gift.” Diagnosed with ALS in 1999, Noël continued to work full-time as deputy governor of the Bank of Canada, showing up each day with his ventilator and wheelchair until his death in 2001.To honor Noël, the ALS Society of Canada established the Tim E. Noël Fellowship in ALS Research in 2006. This is a partnership between the ALS Society of Canada and the Canadian Institutes of Health Research’s Institute of Neurosciences, Mental Health and Addiction, which recognizes and supports post-doctoral ALS researchers by awarding each recipient up to $55,000 annually for a maximum of three years.
Untangling the mystery of disorganized filaments
Rodolphe Perrot, PhD, is the Tim E. Noël Fellowship’s 2008 recipient. With the guidance of Jean-Pierre Julien, PhD, Canada Research Chair in the Mechanisms of Neurodegeneration and Professor of Anatomy and Physiology at the Centre Hospitalier de l'Université Laval (CHUL) Research Centre, Québec, Perrot is working on his project titled “The study of pathogenic mechanisms associated with the disorganization of neuronal cytoskeleton.”
The neuronal cytoskeleton is an interior scaffold that helps to maintain the shape of neurons. It is composed of three interconnected parts: actin microfilaments, microtubules and intermediate filaments. Accumulations of disorganized intermediate filaments are the hallmark of many neurodegenerative disorders including ALS and Parkinson’s disease. However, why or how the intermediate filaments become disorganized is unknown.
Perrot received his doctoral degree from University of Angers, France, where his research focus was neurofilaments, a family of intermediate filaments. “During my doctoral studies, I analyzed the function of neurofilaments in normal conditions,” says Perrot. “I now wish to focus my studies on disease-associated aspects of the neuronal cytoskeleton.” He shifted his research focus to ALS because he felt that the disease deserved more attention. Building on his knowledge of the neuronal cytoskeleton, Perrot hypothesizes that abnormal intermediate filaments can influence fast axonal transport, an important process by which the neuron transports molecules along its axon.
Using mouse models that display various intermediate filament abnormalities, Perrot will capture time-lapsed images of axonal transport of mitochondria and lysosomes. The two organelles are chosen for their critical functions in the neuron: mitochondria generate energy for cellular activities and regulate calcium concentration, whereas lysosomes degrade cellular waste. Perrot will collaborate with Jasna Kriz, MD, PhD, Assistant Professor at the CHUL Research Centre. “They have a new, non-invasive imagery system that enables the measurement of bioluminescence intensity in vivo. Thus we could analyze axonal transport directly in our models,” Perrot explains.
Cytoskeleton proteins play multiple roles in neurons, such as providing structural organization for the cell interior and assisting with transporting materials within the cell. Perrot will therefore also analyze the expression and distribution of cytoskeleton proteins in a different set of mouse models, and try to understand how they affect axonal transport.
With growing evidence that intermediate filament accumulations are directly involved in causing ALS symptoms, researchers are working hard to better understand the cascade of cellular events leading to the disease. Perrot believes that insight into cytoskeleton abnormalities may one day allow the design of targeted pharmacological interventions for both inherited and sporadic forms of ALS.
Calcium toxicity: another clue in SOD1 motor neuron death
Other recipients of the Tim E. Noël Fellowship are making great strides with their research. Sherif Elbasiouny, PhD, at Northwestern University, Illinois, received the award in 2007. His two-part research is titled “Ionic mechanisms underlying motoneuron degeneration in ALS.”
In his first project, which is now complete, Elbasiouny used computer simulations to investigate changes in the physical and electrical properties of motor neurons (also called motoneurons) expressing mutant superoxide dismutase-1 (SOD1), the only confirmed cause of an inherited form of ALS. The study was inspired by recent reports of mutant SOD1 motor neurons that became enlarged and developed complex dendritic structure shortly after birth, but long before the onset of ALS symptoms in transgenic mice. “Learning more about these early alterations in motor neuron properties before their degeneration is critical to understanding ALS pathogenesis,” says Elbasiouny.
Indeed, he found that changes in the size and shape of mutant SOD1 motor neurons accounted for changes in their electrical properties. But this was not the whole story. Elbasiouny also observed a large amount of calcium ions rushing into the mutant motor neuron as it generated electrical impulses. This resulted in a much greater concentration of calcium than in normal motor neurons, which quickly led to calcium toxicity and cell death.
This project was a great success, with results presented at ALS Canada’s 4th Research Forum, held in Toronto, and the “Mechanisms of Plasticity and Disease in Motoneurons” conference in Seattle. A research paper on this study is expected to be completed by the end of 2008.
Influence of drugs and neuromodulators on motor neuron
Elbasiouny is now working on his second project under the guidance of Charles Heckman, PhD, Professor of Physiology at Northwestern University. He has developed an in vitro sacral cord preparation to directly measure electrical properties of motor neurons in the presence of various drugs including Riluzole, the drug currently used to treat ALS.
Elbasiouny will also examine the effect of two neuromodulators -- serotonin and norepinephrine. Neuromodulators are chemical substances released in the brain and spinal cord to modulate the excitability and firing activity of neurons. Since excitability is a feature closely related to degeneration of mutant SOD1 motor neurons, the relationship between neuromodulators and motor neuron survival is worth examining.
Elbasiouny hopes to identify the exact electrical stimulation and pharmacological approaches that can modulate electrical properties of motor neurons. “My main motivation and research interest is to help individuals with disabilities or neurological diseases,” says Elbasiouny, who hopes to set up his own ALS research lab after the post-doctoral training. “The pharmacological results could suggest new drugs to be tested in human clinical trials.”
Antibodies may lead to effective vaccination and diagnostic tool
The first Tim E. Noël Fellowships were awarded to François Gros-Louis, Edor Kabashi and Joe Chakkalakal in 2006. All of them report tremendous progress in their research.
The project of François Gros-Louis, PhD, is titled “Identification of misfolded proteins associated with sporadic ALS through innovative proteomics approaches.” He reached an important milestone when he was part of a research group that successfully synthesized antibodies to recognize misfolded human SOD1 proteins in transgenic mice. “The antibody is a valuable tool for studying proteins,” he explains from the lab of Jean-Pierre Julien at the CHUL Research Centre. “Since we are directly looking for misfolded proteins instead of gene defects, we call this a proteomic-based approach.”
Using the same antibodies, Gros-Louis also identified misfolded SOD1 proteins in the spinal cord tissues of people who died of familial (inherited) or sporadic ALS. This was surprising, since the antibodies managed to detect misfolded SOD1 proteins even though they were targeted to the mutated forms only. Based on preliminary results, Gros-Louis now thinks that misfolded SOD1 proteins exist in some cases of sporadic ALS.
At the same time, other members of the Julien research group showed that misfolded SOD1 proteins could be secreted outside motor neurons. They also demonstrated that post-translational modifications such as oxidation could give normal SOD1 proteins toxic properties similar to those observed in the mutant forms.
The success of Gros-Louis’s research has led to several new developments including an antibody vaccination for SOD1 mutation-linked ALS. “Chromogranins (molecules secreted by nerve cells) engage in specific interactions with different mutant forms of SOD1. Based on this observation, we have proposed a new ALS disease model and tested active immunization protocols that successfully delayed disease onset and increased survival in an ALS mouse model,” Gros-Louis explains.
“However, passive immunization may be safer since administration of antibodies may be stopped at any time if the recipient shows adverse symptoms during treatment,” he adds. “In the passive approach, antibodies are transferred or infused into the person with ALS. This is contrasted to active immunization, where we help the immune system generate its own antibodies. We’ve tested the passive approach in mice and found that our antibodies were also effective in delaying disease onset and increasing survival. More tests need to be done before we can develop immunotherapy for humans, but this is really exciting news.”
As the next step, Gros-Louis will try to identify misfolded SOD1 proteins in blood or cerebrospinal fluid – samples readily available from people living with ALS. “It is imperative to fully characterize the antibodies we have developed,” he says. “These antibodies were generated in mice, so we need to ‘humanize’ them to avoid drastic and lethal immunological effects.”
In addition to treatments, the new antibodies may eventually form the basis of new diagnostic tools for detecting ALS at the early stages or monitoring disease progression. For now, the antibodies are giving researchers like Gros-Louis a better picture of ALS caused by mutant or misfolded SOD1 proteins. “We now have in our hands the tools to understand the pathogenic mechanism,” he says.
New gene mutation gives insight into neuron death
Edor Kabashi, PhD, is attempting to understand ALS from different perspectives. A post-doctoral fellow of Guy Rouleau, MD, PhD, Professor of Medicine at the Université de Montréal, Kabashi has thus far contributed to studies that were published in high-impact journals such as Nature Genetics, Annals of Neurology, Human Molecular Genetics and Journal of Neurochemistry.
In his project, “Developing and characterizing novel models of ALS and other neurological disorders in zebrafish,” Kabashi developed two animal models to investigate the function of a protein called alsin, which is encoded by the Als2 gene. Mutations of Als2 are associated with juvenile ALS, a rare form of the disease. The Als2 gene was “knocked out” or engineered to be non-functional in the mouse model, whereas in the zebrafish model, the gene was only “knocked down” and showed limited expression. By comparing the levels of neurodegeneration in the two models, Kabashi and colleagues identified a variation of mRNA (messenger RNA which contains protein-encoding information) that seemed to prevent and regulate severe neurodegeneration symptoms.
During his doctoral studies, Kabashi worked with Heather Durham, PhD, Professor at McGill University, Montreal, to examine the role of proteasomes in SOD1 mutation-linked inherited ALS. Proteasomes are protein complexes that belong to cellular pathways responsible for handling misfolded, damaged or mutant proteins. In analyzing the mechanisms of proteasomes in ALS mouse models, Kabashi found that structural changes were the main reason for the proteasome’s reduced ability to break down unwanted proteins.
One of Kabashi’s greatest successes as a post-doctoral fellow has been his role as the co-investigator in the discovery of TDP-43 gene mutations in both sporadic and inherited ALS. Although the protein product of TDP-43 is still not well understood by scientists, it is a major component of protein inclusions, or clumps of proteins, in the brains of people with ALS and frontotemporal dementia (FTD). Working with PhD candidate Paul Valdmanis and other Canadian and French researchers to screen the genes of 200 ALS patients, Kabashi identified eight distinct mutations in nine individuals with sporadic or inherited ALS. The new report of TDP-43 gene mutations provides additional evidence for the role of this protein in causing motor neurons to degenerate.
With this discovery, Kabashi plans to study the functional role of TDP-43 in diseased cellular and animal models. “Training with Dr. Guy Rouleau has given me a better understanding of ALS as a clinical disease,” he says. “In my previous research, I worked mainly with animal and cellular models of ALS. During the last two years, I’ve had the chance to meet people with ALS and their families, which gave me a perspective of what a difficult disease ALS is. This certainly inspires me to continue with my research.”
Understanding the connection between neurons and muscles
Joe Chakkalakal, PhD, is a post-doctoral fellow of Joshua Sanes, PhD, Professor of Molecular and Cellular Biology at Harvard University in Boston, Massachusetts. His project is called “The establishment of motor unit homogeneity during development and after axon regeneration.” Using imaging technology and transgenic ALS mouse models, Chakkalakal hopes to better understand how motor neurons and muscle fibres communicate during normal development and after injury. Together, a motor neuron and the muscle fibres that it innervates form the motor unit.
“I have characterized two BAC transgenic fluorescent reporter mouse models to track the development and patterning of muscle fibres,” says Chakkalakal of his major success thus far. BAC stands for bacterial artificial chromosome, a molecular technique that allows the direct study of gene expression in animal disease models. BAC contains the gene of interest and a reporter gene that acts as an easily identifiable and measurable marker. The reporter gene in Chakkalakal’s mouse models produces fluorescent proteins that glow under specific lighting.
The slow motor neuron is a type of neuron that releases small amounts of neurotransmitters to generate small contractions in muscle fibres. As the signal-carrying neurotransmitters accumulate, the muscle contractions gradually become more intense. “It seems that particular types of motor units, such as the slow type, are relatively resistant to pathological consequences of ALS,” explains Chakkalakal. “It’s therefore important to understand how slow motor units develop and what makes them resist disease progression.”
Chakkalakal decided to give the slow motor unit a closer look and studied the synaptic vesicle protein 2 (SV2), which is secreted by neurons into the point of connection between motor neuron and muscle fibre. He soon isolated a specific form of SV2 that was selectively expressed in slow motor neurons. Analyzing slow motor units during development and after injury is difficult due to the lack of techniques to do so, but this challenge may soon be overcome with Chakkalakal’s discovery of the specific SV2. “This may help identify potential therapeutic targets and perhaps prevent disease progression of ALS,” he says.
“We now have a model system to help us come up with strategies to observe how neurons develop, respond to insult and behave in neurodegenerative disorders,” continues Chakkalakal, whose direction in ALS research stems from his interest in the development of motor units. “Some of the remaining challenges include using transgenic mouse models to understand the behaviour of particular types of motor neurons and motor units in response to damage or disease.”
In the coming years, the Tim E. Noël Fellowship will continue to leverage funds and encourage young scientists to pursue ALS research. With the award recipients’ passion and commitment to ALS research, our knowledge of ALS is significantly advancing.
| Posted On: Wednesday, October 22, 2008 Modified: Wednesday, May 27, 2009 Category: Researchers Posted By: |