\ ALS Research \ TDP-43 mutations cause ALS and FTLD-like disease in mice
Mice expressing a gene mutation known to cause amyotrophic lateral sclerosis and frontotemporal lobar degeneration exhibit behavioral and pathological features resembling the human diseases, researchers at Washington University School of Medicine in St. Louis report.
The study, published in the Proceedings of the National Academy of Science in October 2009, suggests that the mechanisms underlying the selective death of neurons in ALS and FTLD are similar in mice and in humans.
Mice expressing mutant TAR DNA-binding protein of 43 kilodaltons (TDP-43) were generated after similar mutations were reported in patients with familial (hereditary) and sporadic ALS. Researchers hope that the mice might be useful in the study of both forms of the disease. Like patients, the mice go on to develop progressive neurodegenerative disease leading to death.
TDP-43 is a protein that can bind to other proteins and change the way they function, but it can also bind to pieces of DNA and RNA to regulate the way proteins are expressed. Its identification in 2006 as a component of protein clumps inside dying neurons in ALS and FTLD challenged the way researchers thought about the diseases. Since then, scientists have been trying to figure out how this abnormal protein might be killing neurons.
The development of a mouse model of TDP-43-mediated neurodegeneration was an essential step. This would allow senior author Robert Baloh, MD, PhD, assistant professor of neurology, and his group to examine how the TDP-43 mutation was changing the protein’s function, and the functions of other cellular constituents that it might bind to.
The TDP-43 mutation caused signs of ALS-like disease in mice as early as three months. The mice, which would normally live for two years or more, died after five months.
Although the disease resembled ALS behaviorally, Baloh and his group hoped they would see pathological similarities inside the dying neurons of the brain and spinal cord too.
They did. Remarkably, despite the expression of mutant TDP-43 in every neuron in the nervous system, only the specific neurons that succumb to degeneration in ALS and FTLD exhibited the characteristic protein clumps. This suggests that the mechanism underlying the selective vulnerability of specific neurons in ALS and FTLD is the same in mice.
But when they looked more closely at the protein clumps inside these neurons, they saw something they didn’t expect.
Although the degenerating neurons in the TDP-43 mutant transgenic mice contained protein clumps, TDP-43 was not part of them. This suggests that the neurodegeneration induced by TDP-43 mutations is not related to toxic aggregation of the protein itself.
In light of recent reports of mutations in another RNA-binding protein, fused in liposarcoma (FUS), in ALS patients, Baloh and his colleagues suggested that TDP-43 mutations might interfere with the protein’s RNA-binding ability leading to disruptions in protein degradation pathways. This means that the protein clumps inside dying neurons in ALS and FTLD being might in fact be the byproduct of the cell’s inability to break down and get rid of abnormal proteins.
SOD1 mutant transgenic mice are the most widely used animal model for ALS research. They were generated after the identification of mutations in the first gene shown to cause familial ALS – superoxide dismutase 1 (SOD1). The mice develop ALS-like disease and die within four to 14 months depending on the mutation. Like the TDP-43 mutant transgenic mice, their dying motor neurons contain the typical protein clumps. But despite more than a decade of research using SOD1 mutant transgenic mice, the mechanism by which SOD1 mutations cause ALS remains unknown. Researchers hope that comparing SOD1 mutant transgenic mice with TDP-43 mutant transgenic mice will shed some light on common disease pathways – some of which might involve RNA binding.
The study was funded the National Institutes of Health, the Neuroscience Blueprint Core, the Hope Center for Neurological Disorders, the McDonnell Center for Cellular and Molecular Neurobiology, the Muscular Dystrophy Association and the Children’s Discovery Institute.
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TDP-43 mutations cause ALS and FTLD-like disease in mice
By Katie Moisse, PhDMice expressing a gene mutation known to cause amyotrophic lateral sclerosis and frontotemporal lobar degeneration exhibit behavioral and pathological features resembling the human diseases, researchers at Washington University School of Medicine in St. Louis report.
The study, published in the Proceedings of the National Academy of Science in October 2009, suggests that the mechanisms underlying the selective death of neurons in ALS and FTLD are similar in mice and in humans.
Mice expressing mutant TAR DNA-binding protein of 43 kilodaltons (TDP-43) were generated after similar mutations were reported in patients with familial (hereditary) and sporadic ALS. Researchers hope that the mice might be useful in the study of both forms of the disease. Like patients, the mice go on to develop progressive neurodegenerative disease leading to death.
TDP-43 is a protein that can bind to other proteins and change the way they function, but it can also bind to pieces of DNA and RNA to regulate the way proteins are expressed. Its identification in 2006 as a component of protein clumps inside dying neurons in ALS and FTLD challenged the way researchers thought about the diseases. Since then, scientists have been trying to figure out how this abnormal protein might be killing neurons.
The development of a mouse model of TDP-43-mediated neurodegeneration was an essential step. This would allow senior author Robert Baloh, MD, PhD, assistant professor of neurology, and his group to examine how the TDP-43 mutation was changing the protein’s function, and the functions of other cellular constituents that it might bind to.
The TDP-43 mutation caused signs of ALS-like disease in mice as early as three months. The mice, which would normally live for two years or more, died after five months.
Although the disease resembled ALS behaviorally, Baloh and his group hoped they would see pathological similarities inside the dying neurons of the brain and spinal cord too.
They did. Remarkably, despite the expression of mutant TDP-43 in every neuron in the nervous system, only the specific neurons that succumb to degeneration in ALS and FTLD exhibited the characteristic protein clumps. This suggests that the mechanism underlying the selective vulnerability of specific neurons in ALS and FTLD is the same in mice.
But when they looked more closely at the protein clumps inside these neurons, they saw something they didn’t expect.
Although the degenerating neurons in the TDP-43 mutant transgenic mice contained protein clumps, TDP-43 was not part of them. This suggests that the neurodegeneration induced by TDP-43 mutations is not related to toxic aggregation of the protein itself.
In light of recent reports of mutations in another RNA-binding protein, fused in liposarcoma (FUS), in ALS patients, Baloh and his colleagues suggested that TDP-43 mutations might interfere with the protein’s RNA-binding ability leading to disruptions in protein degradation pathways. This means that the protein clumps inside dying neurons in ALS and FTLD being might in fact be the byproduct of the cell’s inability to break down and get rid of abnormal proteins.
SOD1 mutant transgenic mice are the most widely used animal model for ALS research. They were generated after the identification of mutations in the first gene shown to cause familial ALS – superoxide dismutase 1 (SOD1). The mice develop ALS-like disease and die within four to 14 months depending on the mutation. Like the TDP-43 mutant transgenic mice, their dying motor neurons contain the typical protein clumps. But despite more than a decade of research using SOD1 mutant transgenic mice, the mechanism by which SOD1 mutations cause ALS remains unknown. Researchers hope that comparing SOD1 mutant transgenic mice with TDP-43 mutant transgenic mice will shed some light on common disease pathways – some of which might involve RNA binding.
The study was funded the National Institutes of Health, the Neuroscience Blueprint Core, the Hope Center for Neurological Disorders, the McDonnell Center for Cellular and Molecular Neurobiology, the Muscular Dystrophy Association and the Children’s Discovery Institute.
| Posted On: Tuesday, November 17, 2009 Modified: Tuesday, November 17, 2009 Category: ALS Research Posted By: |