\ ALS Research \ TDP-43 mutations cause motor deficits in zebrafish
Mutations in the TAR DNA-binding protein (TDP-43) gene cause motor neuron defects in zebrafish and lead to impaired swimming, researchers from Université de Montreal report. Interestingly, insufficient TDP-43 expression leads to similar abnormalities, suggesting that both a gain of toxic function through mutations and a loss of normal TDP-43 function might contribute to neurodegeneration in ALS.
Mutations in the gene encoding TDP-43 – a protein that aggregates inside dying motor neurons in ALS – have been reported in patients with both familial (hereditary) and sporadic (of unknown origin) forms of the disease. This prompted Edor Kabashi, PhD, to investigate how these mutations affect motor neuron function – first in cell culture – then in zebrafish.
When Kabashi expressed mutant TDP-43 in cultured motor neurons, he observed aggregates – or protein clumps – inside the cells, reminiscent of those seen in the motor neurons of patients with ALS. This effect was specific to motor neuron cultures and was absent when the mutant gene was expressed in other cell types of cultured cells.
Based on these results, Kabashi expressed the mutant gene in zebrafish to see whether motor neuron-specific abnormalities would occur in a living system, and whether they would translate into impaired movement. He found that mutant TDP-43 expression resulted in motor neuron defects, including shorter axons (the part of the neuron that transmits signals) and abnormal axonal branching. When he examined the effects on movement, he observed impaired swimming in the absence of sensory deficits, suggesting that TDP-43 mutations preferentially target motor neurons for degeneration.
TDP-43 is essential, according to previous reports. Without it, cells cannot function and organisms cannot survive. Using his zebrafish model, Kabashi investigated the effects of decreasing, as opposed to eliminating, TDP-43 expression during development. He observed motor neuron defects similar to those associated with mutant TDP-43 expression, which could be eliminated by restoring normal TDP-43 levels. Restoration with mutant TDP-43 did not rescue the zebrafish, providing further evidence that mutations in TDP-43 alter its normal function.
The study, recently published in the journal Human Molecular Genetics, provides evidence that mutant TDP-43 is harmful to motor neurons both through a loss of normal TDP-43 function as well as a gain of toxic function. It also highlights similarities between the protein’s involvement in development and degeneration, which may help researchers understand its role in ALS.
Kabashi is a recipient of the Tim E. Noël Fellowship in ALS Research. The award, established in honour of the former deputy governor of the Bank of Canada, is a partnership between the ALS Society of Canada and the Canadian Institutes of Health Research’s Institute of Neurosciences, Mental Health and Addiction.
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TDP-43 mutations cause motor deficits in zebrafish
By Katie Moisse, PhDMutations in the TAR DNA-binding protein (TDP-43) gene cause motor neuron defects in zebrafish and lead to impaired swimming, researchers from Université de Montreal report. Interestingly, insufficient TDP-43 expression leads to similar abnormalities, suggesting that both a gain of toxic function through mutations and a loss of normal TDP-43 function might contribute to neurodegeneration in ALS.
Mutations in the gene encoding TDP-43 – a protein that aggregates inside dying motor neurons in ALS – have been reported in patients with both familial (hereditary) and sporadic (of unknown origin) forms of the disease. This prompted Edor Kabashi, PhD, to investigate how these mutations affect motor neuron function – first in cell culture – then in zebrafish.
When Kabashi expressed mutant TDP-43 in cultured motor neurons, he observed aggregates – or protein clumps – inside the cells, reminiscent of those seen in the motor neurons of patients with ALS. This effect was specific to motor neuron cultures and was absent when the mutant gene was expressed in other cell types of cultured cells.
Based on these results, Kabashi expressed the mutant gene in zebrafish to see whether motor neuron-specific abnormalities would occur in a living system, and whether they would translate into impaired movement. He found that mutant TDP-43 expression resulted in motor neuron defects, including shorter axons (the part of the neuron that transmits signals) and abnormal axonal branching. When he examined the effects on movement, he observed impaired swimming in the absence of sensory deficits, suggesting that TDP-43 mutations preferentially target motor neurons for degeneration.
TDP-43 is essential, according to previous reports. Without it, cells cannot function and organisms cannot survive. Using his zebrafish model, Kabashi investigated the effects of decreasing, as opposed to eliminating, TDP-43 expression during development. He observed motor neuron defects similar to those associated with mutant TDP-43 expression, which could be eliminated by restoring normal TDP-43 levels. Restoration with mutant TDP-43 did not rescue the zebrafish, providing further evidence that mutations in TDP-43 alter its normal function.
The study, recently published in the journal Human Molecular Genetics, provides evidence that mutant TDP-43 is harmful to motor neurons both through a loss of normal TDP-43 function as well as a gain of toxic function. It also highlights similarities between the protein’s involvement in development and degeneration, which may help researchers understand its role in ALS.
Kabashi is a recipient of the Tim E. Noël Fellowship in ALS Research. The award, established in honour of the former deputy governor of the Bank of Canada, is a partnership between the ALS Society of Canada and the Canadian Institutes of Health Research’s Institute of Neurosciences, Mental Health and Addiction.
| Posted On: Thursday, January 07, 2010 Modified: Thursday, January 07, 2010 Category: ALS Research Posted By: |