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Going Wild About the Latest TDP-43 Mouse Models
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4 February 2010. Rodents and fruit flies and worms, oh my! The new animal models for TDP-43 proteinopathies, a series of related neurodegenerative diseases, are coming out at a fast and furious rate. The latest to debut, published online this week by PNAS, are mouse models from researchers at the VIB-University of Antwerp in Belgium. The scientists report a set of mice that express wild-type, human TDP-43 in neurons. The work was led by first author Hans Wils and senior authors Christine Van Broeckhoven and Samir Kumar-Singh in Van Broeckhoven’s laboratory.
“This is the first mouse model that has TDP-43 inclusions,” Kumar-Singh said. “This is going to be a very powerful series of animal models that can be used for eventual drug targeting.” The mice are also the first wild-type TDP-43 overexpression strains to be published; last October Robert Baloh and colleagues at Washington University in St. Louis, Missouri, reported on a mouse carrying human TDP-43 with the disease-linked mutation A315T (see ARF related news story on Wegorzewska et al., 2009). Other animal models under development include rats, zebrafish, fruit flies, and nematodes (see ARF related news story). “The avalanche has begun,” quipped Brian Kraemer of the University of Washington in Seattle. Kraemer was not involved with the current study but has his own TDP-43 knockout mouse in the works. The fish, flies, and worms offer powerful genetic platforms to explore the normal functions of TDP-43; the rodents, it is hoped, will provide systems more akin to human biology.
In people, TDP-43 proteinopathies encompass a spectrum of diseases including some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Researchers have discovered several TDP-43 mutations in some people with ALS, but in most cases of TDP-43 proteinopathy, it is the wild-type protein that aggregates and is linked to neurodegeneration. The new mouse models may best mimic these sporadic cases, Kumar-Singh said. In that way it parallels a Drosophila model published recently, which also showed neurodegeneration from the wild-type protein (see ARF related news story). Ronald Klein and colleagues at the Louisiana State University Health Sciences Center in Shreveport also showed that the wild-type protein could be destructive in rodents. They reported last year on a rat model, produced by injecting a viral vector carrying the wild-type TDP-43 gene into the substantia nigra (see ARF related news story on Tatom et al., 2009).
Wils and colleagues created transgenic mice expressing human TDP-43 driven by the neuron-specific mouse Thy-1 promoter, which activates approximately one week after birth. They used multiple mouse lines to analyze the animals’ response to different “doses” of human TDP-43. Of the lines they initially made, the two highest expressers made 1.9- and 2.8-fold more TDP-43 than non-transgenic mice, according to immunohistochemistry analyses. The researchers then self-crossed each line to create homozygotes that expressed approximately double that again, 3.8- and 5.1-fold more TDP-43 than non-transgenics. (At the RNA level, quantitative PCR analysis showed that the animals had 0.6- to 1.2-fold of the human TDP-43 gene, compared to the endogenous mouse gene.)
Mice with the greatest TDP-43 load developed their first symptom, abnormal hindlimb reflexes, by just two weeks of age. Symptoms progressed to include stumbling, impaired performance on the rotarod test, and facial muscle spasms. These animals died within a month of birth. The mice expressing 3.8-fold normal TDP-43 evinced hindlimb symptoms at two months, and survived for nearly seven months. The 2.8-fold animals had normal reflexes until 14 months of age. Kumar-Singh and colleagues euthanized these animals before determining their survival rate, but in more recent studies, some of them have survived to 20 months or more, he told ARF in an e-mail. The researchers have not noticed any symptoms in the lowest, 1.9-fold expressers, which they have followed for 19 months. Degeneration of motor neurons, characteristic of ALS, and cortical neurons, as in FTLD, was similarly dose dependent.
TDP-43 appears to be a Goldilocks protein: too much or too little is lethal; a certain amount is just right. Other researchers attempting to make TDP-43 mice have found the project challenging due to the narrow window between getting no phenotype and getting a lethal one. “It tells me that TDP-43 is very well controlled,” Kumar-Singh said. Baloh noted that using the Thy-1 promoter as Wils and colleagues did is a promising approach because the transgene is not activated until after birth, so the excess TDP-43 does not interfere with early development.
How might these models relate to the human disease? There is no evidence that people with TDP-43 proteinopathy have abnormally high levels of the protein, but Kumar-Singh theorized that just a little extra TDP-43, over the course of a lifetime, could make neurons vulnerable. Similarly, he noted, increased levels of amyloid precursor protein—due to duplication or trisomy—can increase the protein’s dose and cause Alzheimer disease. Because levels of the protein are so tightly controlled, simple gene duplication is unlikely to explain TDP-43 proteinopathies. However, Kumar-Singh suggested that polymorphisms in the untranslated regions flanking the TDP-43 gene, or in a gene that influences its expression, might cause increased production. Researchers have already found a variant in the TDP-43 untranslated region in a person who had FTLD (Gitcho et al., 2009).
Mouse vs. Mouse
The TDP-43 field now has both wild-type TDP-43 and mutant mouse models, but “I would not say they are a matched pair,” Baloh said. They are closer than apples and oranges, more like “oranges and tangerines,” he said. Baloh and his colleagues used the mouse prion promoter PrP, which activates expression in glia as well as neurons. They saw TDP-43 levels approximately three times that of endogenous protein, although these data are not directly comparable to the Wils data because they are based on lysate analysis, not immunohistochemistry. But like Kumar-Singh’s, Baloh’s animals were ill. They suffered motor symptoms by three or four months and lived for an average of five months.
Although human TDP-43 is present throughout the brain in models from both groups, certain neuronal populations were particularly sensitive to the transgene. Layer V cortical neurons, including the primary motor cortex, as well as spinal motor neurons, were hard hit in both models. By confirming Baloh’s observations, the new publication shows that the effects on the cortex were not specific to one line. “That is really exciting,” Baloh said. “What is it about those neurons that are so vulnerable to TDP-43 toxicity?”
A key hallmark of TDP-43 proteinopathy is aggregates containing ubiquitin and phosphorylated TDP-43. The Baloh group observed aggregates, but the accumulations did not contain TDP-43. Van Broeckhoven and colleagues, in contrast, observed that nuclear aggregates, and some cytoplasmic aggregates, in their highest-expressing mice were positive for phosphorylated TDP-43 and ubiquitin. The difference may not be major, Baloh suggested. He noted that the Van Broeckhoven mice were much sicker than his at the time they were sacrificed for immunostaining. The two groups also used different antibodies, and Baloh thinks that with the right antibodies, he, too, might see the occasional TDP-43-positive aggregate in his mice.
In TDP-43 proteinopathy, the normally nuclear protein tends to abandon the nucleus for the cytoplasm. Baloh and colleagues noted occasional, but not widespread, nuclear clearing of TDP-43. The Kumar-Singh group noticed TDP-43 inclusions in both the nucleus and cytoplasm. Caspase-based cleavage of TDP-43, releasing a 25-kDa carboxyl-terminal fragment, has also been linked to the protein’s toxicity (see ARF related news story on Zhang et al., 2009). Both wild-type and mutant TDP-43 mice showed evidence of these damaging fragments as well. The Van Broeckhoven group compared nuclear and cytoplasmic fractions and discovered the fragments were primarily nuclear in their mice, an unexpected finding given the usual association between cytoplasmic localization and cytotoxicity.
“This is the best TDP-43 animal model to date, because it is a mouse and wild-type TDP-43,” Klein wrote of Kumar Singh’s work in an e-mail to ARF. This will certainly not be the last model, but with just Kumar-Singh’s and Baloh’s work to go on, the question remains: Did the A315T mutation in Baloh’s model cause disease, or are those mice sick simply because of overexpression of TDP-43 itself, as in Kumar-Singh’s strain? To solve that conundrum, Baloh said, will require a matched pair of mice with wild-type or mutant TDP-43, under the same promoter, at the same level of expression. Kumar-Singh reported that the group has an as-yet-unpublished mutant TDP-43 line that is similar to Baloh’s strain.
“There is never a single mouse that will do everything,” said John Trojanowski of the University of Pennsylvania in Philadelphia. “It is inevitably the case that you need more than one transgenic mouse to model a disease.” His laboratory is pursuing its own mouse model, with a different strategy. Their results are different from, but complementary to, the published mouse models, Trojanowski told ARF.
A single species cannot do everything, either, Kraemer noted. Mice will be useful for the final tests of promising therapeutics, but to find those potential treatments, researchers will need to perform high-throughput screens in vitro or with smaller, cheaper animals—such as worms, flies, and fish.
“The optimistic thing for patients and families is that the pace of research is going so much more rapidly now,” Trojanowski said. In comparison, he noted, tau was discovered to be a component of tangles in the mid-1980s, but mouse models were not available until the end of the 1990s. TDP-43 was linked to disease in 2006 (see ARF related news story on Neumann et al., 2006), and four years later scientists can pick and choose from a plethora of model systems.—Amber Dance.
Reference:
Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frototemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63. Abstract
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Related Paper: A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity.
Comment by: Lary Walker, ARF Advisor
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Submitted 5 May 2008
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Posted 6 May 2008
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 I recommend this paper
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Related Paper: A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity.
Comment by: Jurgen Gotz
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Submitted 9 May 2008
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Posted 9 May 2008
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I recommend this paper
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Related News: New Ubiquitinated Inclusion Body Protein Identified
Comment by: Julene K. Johnson
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Submitted 12 October 2006
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Posted 12 October 2006
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From a clinical perspective, the identification of TDP-43 protein represents a major breakthrough in our understanding of both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The TDP-43 is the mystery protein that is associated with the ubiquitin-positive inclusions that are commonly found in many patients with FTLD and in most, if not all, patients with ALS.
This finding is particularly important because several recent papers suggest that patients who have FTLD with ubiquitin inclusions at autopsy (FTLD-U) account for approximately 50 percent of all autopsy-confirmed FTLD cases (1-3). The remaining majority of FTLD cases are associated with the tau protein, but other neuropathological diagnoses exist. The finding that possibly one-half of all FTLD patients may have ubiquitin-positive neuropathology means that any breakthroughs in the biology of this protein could potentially translate into helping a large proportion of FTLD patients.
In addition, the finding that the TDP-43 protein is also found in patients with ALS further supports...
Read more
From a clinical perspective, the identification of TDP-43 protein represents a major breakthrough in our understanding of both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The TDP-43 is the mystery protein that is associated with the ubiquitin-positive inclusions that are commonly found in many patients with FTLD and in most, if not all, patients with ALS.
This finding is particularly important because several recent papers suggest that patients who have FTLD with ubiquitin inclusions at autopsy (FTLD-U) account for approximately 50 percent of all autopsy-confirmed FTLD cases (1-3). The remaining majority of FTLD cases are associated with the tau protein, but other neuropathological diagnoses exist. The finding that possibly one-half of all FTLD patients may have ubiquitin-positive neuropathology means that any breakthroughs in the biology of this protein could potentially translate into helping a large proportion of FTLD patients.
In addition, the finding that the TDP-43 protein is also found in patients with ALS further supports the overlap between FTLD and ALS. Future research on the TDP-43 protein will likely also benefit ALS patients and help us understand how these two very different clinical phenotypes are related.
References:
1. Lipton AM, White CL 3rd, Begio EH. Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol (Berl). 2004 Nov;108(5):379-85. Abstract
2. Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, Chute DS, Roberson ED, Pace-Savitsky C, Neumann M, Chow TW, Rosen HJ, Forstl H, Kurz A, Miller BL.. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Archives of Neurology. 2005;62:925-930. Abstract
3. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee V M-Y, Miller BL, Trojanowski JQ, & Grossman M. (2006). Frontotemporal dementia: Clinicopathological correlations. Annals of Neurology. 2006;59:952-962. Abstract
 View all comments by Julene K. Johnson |
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Related News: New Ubiquitinated Inclusion Body Protein Identified
Comment by: David M.A. Mann
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Submitted 12 October 2006
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Posted 12 October 2006
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In this paper, Drs. Lee and Trojanowski and colleagues have at long last identified the mystery protein hiding within the ubiquitinated inclusions that characterize certain histological forms of frontotemporal lobar degeneration (FTLD), termed FTLD-U. This task has challenged neuroscientists for well over a decade, with all prior attempts at identification using immunohistochemical or biochemical methods proving fruitless. The culprit protein is a TAR DNA-binding protein, known as TDP-43. This protein is present within all the ubiquitinated structures in FTLD-U, viz., the neuronal cytoplasmic inclusions, the neuronal intranuclear inclusions, and the neuritic changes, though whether this is the sole component of these structures (other than ubiquitin) remains uncertain. Some previous studies reported the presence of p62 protein within neuronal cytoplasmic inclusions, but such findings have been inconsistent. Moreover, Lee and Trojanowski have shown that the ubiquitinated neuronal cytoplasmic inclusions seen within spinal and cranial nerve nuclear motor neurons in motor neuron...
Read more
In this paper, Drs. Lee and Trojanowski and colleagues have at long last identified the mystery protein hiding within the ubiquitinated inclusions that characterize certain histological forms of frontotemporal lobar degeneration (FTLD), termed FTLD-U. This task has challenged neuroscientists for well over a decade, with all prior attempts at identification using immunohistochemical or biochemical methods proving fruitless. The culprit protein is a TAR DNA-binding protein, known as TDP-43. This protein is present within all the ubiquitinated structures in FTLD-U, viz., the neuronal cytoplasmic inclusions, the neuronal intranuclear inclusions, and the neuritic changes, though whether this is the sole component of these structures (other than ubiquitin) remains uncertain. Some previous studies reported the presence of p62 protein within neuronal cytoplasmic inclusions, but such findings have been inconsistent. Moreover, Lee and Trojanowski have shown that the ubiquitinated neuronal cytoplasmic inclusions seen within spinal and cranial nerve nuclear motor neurons in motor neuron disease (amyotrophic lateral sclerosis) also contain TDP-43.
This is an immensely important study with huge implications for neurobiology.
Firstly, it pinpoints a key biochemical constituent in the pathogenesis of FTLD-U and motor neuron disease (MND), and one which previous work would never have regarded as a likely candidate protein.
Secondly, although an association between FTLD and MND had long been known on account of some cases showing defined clinical features of both disorders, sharing pathological features of both disorders, and families being known where some members had FTLD, others MND, and others the combined disorder, it was never clear whether this association was coincidental or causal. Now we can see causality, and the implication that FTLD and MND are part and parcel of the same disease spectrum will have major ramifications for understanding pathogenesis, and eventual treatment.
Thirdly, the finding of TDP-43 pathological changes in FTLD patients with mutations in the newly identified progranulin (PGRN) gene, who typically show FTLD-U pathological changes, firmly brings together a causal relationship in these two fundamental proteins in driving the pathogenesis of the disorder, and opens up untapped vistas of neurobiological research.
Therefore, in rapid time, two major (protein) pieces in the jigsaw puzzle of FTLD have been identified. The challenge now will be to fit the pieces around these and eventually identify the linking processes that bring these together into the fuller picture. Nonetheless, it is clear that even within FTLD-U there are different histological and clinical phenotypes, and it will be necessary to dissect out biochemical or other factors that might determine where the TDP-43 pathological changes take place in the brain to produce the clinical phenotype. That is, why is it that in some patients the most common clinical manifestation of FTLD-U, frontotemporal dementia, is present in association with bilateral involvement of the frontal and temporal lobes, yet in others only the temporal lobes are affected—producing semantic dementia—and in others the left hemisphere is preferentially affected to give progressive non-fluent aphasia. Also, what determines whether TDP-43 changes will be in the brainstem and spinal cord to give MND, or in the cerebral cortex to give FTLD? Lastly, in all this flurry of excitement, it should not be forgotten that tauopathy is still a major cause of FTLD, and it is not immediately apparent how pathological changes in the expression or function of tau might link in with progranulin and TDP-43. Clearly, changes in all three molecules can produce the same disorder of FTLD either separately or collectively: it is not possible to unequivocally discriminate FTD patients with MAPT mutations from those with PGRN mutations, or others without mutations in either. Interrelationships within this Bermuda triangle of tau, progranulin, and TDP-43 will need to be addressed.
The identification of TDP-43 as a (major/sole) component of the ubiquitinated protein of FTLD and MND, in conjunction with the identification of mutations in PGRN, have opened up huge new fields within the neurobiology of neurodegenerative disease with tentacles that may stretch far wider than these two disorders themselves. Whether there is a role for either or both of these proteins in other disorders like Alzheimer disease and Parkinson disease remains to be seen. The gauntlet has been cast down—it is up to the neuroscience community to pick this up and address these issues. What is certain is that there will be a major change in the focus of neurobiological research as groups worldwide seek to investigate the implications of changes in proteins such as progranulin and TDP-43 in terms of health and disease. We can look forward within the near future to major advances in our understanding of how the brain works in respect of these molecules and why neurodegenerative disease occurs when they fail to function properly. Maybe even a treatment for neurodegenerative disease may come a little closer.
View all comments by David M.A. Mann |
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Related News: New Ubiquitinated Inclusion Body Protein Identified
Comment by: Tetsuaki Arai
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Submitted 14 October 2006
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Posted 18 October 2006
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I recommend the Primary Papers
Neumann, Sampathu, Kwong, and colleagues have resolved a long-standing issue in the research field of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). These authors have identified TDP-43 as a major component of ubiquitin-positive inclusions that characterize these disorders. They first extracted a fraction from the patients' brains using monoclonal antibodies and then analyzed it by mass spectrometry. Their findings have greatly facilitated the understanding of the molecular pathogenesis of FTLD and ALS.
Independently, we have also found TDP-43 as a component of the inclusions in FTLD [1]. Following electrophoresis of the sarkosyl-insoluble brain extracts from FTLD, Alzheimer disease (AD) and dementia with Lewy bodies (DLB), we have done exhaustive analyses by mass spectrometry. Following identification of each molecule that is more abundant in FTLD than AD/DLB, we have studied FTLD brain samples immunochemically and immunohistochemically. The antibodies to TDP-43 have immuno-stained neuronal inclusions and dystrophic neurites in the...
Read more
Neumann, Sampathu, Kwong, and colleagues have resolved a long-standing issue in the research field of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). These authors have identified TDP-43 as a major component of ubiquitin-positive inclusions that characterize these disorders. They first extracted a fraction from the patients' brains using monoclonal antibodies and then analyzed it by mass spectrometry. Their findings have greatly facilitated the understanding of the molecular pathogenesis of FTLD and ALS.
Independently, we have also found TDP-43 as a component of the inclusions in FTLD [1]. Following electrophoresis of the sarkosyl-insoluble brain extracts from FTLD, Alzheimer disease (AD) and dementia with Lewy bodies (DLB), we have done exhaustive analyses by mass spectrometry. Following identification of each molecule that is more abundant in FTLD than AD/DLB, we have studied FTLD brain samples immunochemically and immunohistochemically. The antibodies to TDP-43 have immuno-stained neuronal inclusions and dystrophic neurites in the hippocampus and the temporal cortex in FTLD, and skein-like inclusions in the spinal cord in FTLD and ALS. Immunoblotting of the sarkosyl-insoluble fraction has shown abnormal changes in TDP-43 including hyperphosphorylation, fragment formation, and smear-like staining, all of which are similar to abnormal tau in AD and suggest a central role for the formation of abnormal aggregates. These findings are comparable with those by Lee's group. This is not surprising, since both groups have employed principally the same polyclonal antibody which is the only commercially available rabbit polyclonal.
In addition, however, we have found TDP-43-positive glial inclusions in the spinal cord in FTLD and ALS. These inclusions were also positive for tau. The distribution of glial inclusions was consistent with the degenerating areas, suggesting that glial abnormalities are involved in the pathological processes of ALS and FTLD. A difference between our results and theirs is the TDP-43-positive staining of some, but not all, tau-positive structures including Pick bodies and neurofibrillary tangles. The significance of these findings remains to be established, since immunoblot analysis did not show any abnormality in TDP-43 in Pick disease and Alzheimer disease. Our paper will appear shortly in Biochem Biophys Res Commun [1].
In the case of tau and α-synuclein, detection of abnormally modified molecules has revealed far more extensive pathology than that seen by ubiquitin immunohistochemistry. While lesions immunohistochemically labeled for TDP-43 are a little more numerous than those labeled for ubiquitin, the difference is far less than that we have experienced for tau and α-synuclein immunohistochemistry. This may be a point that remains to be cleared up. Another issue that is open for further investigations is to prove, by protein chemistry, the ubiquitination of TDP-43.
In any event, it has to be emphasized that two different approaches have come to the same conclusion, establishing with certainty that TDP-43 is the major component of the inclusions in FTLD and ALS. This further strengthens the hypothesis that these disorders are part of a clinicopathological spectrum that shares similar pathogenesis, and suggests the possibility that TDP-43 may be a common therapeutic target for these disorders. It is now necessary to investigate the relationship of TDP-43 to other molecules that have been reported to be associated with familial FTD, FTD with motor neuron disease, or ALS. Such molecules include progranulin, charged multivesicular body protein 2B (CHMP2B), valosin-containing protein, dynactin, and an unidentified protein in familial disease linked to chromosome 9.
References:
1. T. Arai, M. Hasegawa, H. Akiyama, K. Ikeda, T. Nonaka, H. Mori, D. Mann, K. Tsuchiya, M. Yoshida, Y. Hashizume, T. Oda, TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis, Biochem Biophys Res Commun, in press
View all comments by Tetsuaki Arai |
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Related News: Meet the First Published TDP-43 Mouse
Comment by: Samir Kumar-Singh
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Submitted 16 October 2009
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Posted 16 October 2009
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This study elegantly gives a first insight on a transgenic mouse model of mutant TDP-43 (A315T) identified in familial ALS patients. For those in the field, it is clear that generating these mouse models is a mammoth task on its own. Among the many interesting findings in this paper, the first to catch my attention was that the 25-kDa TDP-43 C-terminal fragments (CTFs) were recovered from detergent-soluble fractions but not from urea fractions as observed in sporadic and familial ALS/FTLD patients. If the TDP-43 25-kDa CTFs would indeed be confirmed as the real culprit, this would yet again emphasize the importance of soluble but not aggregated protein/peptide in cellular toxicity, as has been shown for a number of other proteinopathies including Aβ, α-synuclein, polyglutamine expansion in Huntingtin, and mutant SOD1.
Another important observation made in this paper was that ubiquitin-immunoreactive (ir) inclusions observed in select neurons including motor neurons were not TDP-43-ir. Thus, the mutant TDP-43 (A315T) mice do not completely model ALS, where...
Read more
This study elegantly gives a first insight on a transgenic mouse model of mutant TDP-43 (A315T) identified in familial ALS patients. For those in the field, it is clear that generating these mouse models is a mammoth task on its own. Among the many interesting findings in this paper, the first to catch my attention was that the 25-kDa TDP-43 C-terminal fragments (CTFs) were recovered from detergent-soluble fractions but not from urea fractions as observed in sporadic and familial ALS/FTLD patients. If the TDP-43 25-kDa CTFs would indeed be confirmed as the real culprit, this would yet again emphasize the importance of soluble but not aggregated protein/peptide in cellular toxicity, as has been shown for a number of other proteinopathies including Aβ, α-synuclein, polyglutamine expansion in Huntingtin, and mutant SOD1.
Another important observation made in this paper was that ubiquitin-immunoreactive (ir) inclusions observed in select neurons including motor neurons were not TDP-43-ir. Thus, the mutant TDP-43 (A315T) mice do not completely model ALS, where ubiquitin-ir inclusions are also TDP-43-ir; nevertheless, this work does lead to a very interesting question: what are these inclusions composed of?
Knowing earlier studies (see Tatom et al., 2009 and ARF related news story), I am also not surprised at the glaring omission of wild-type TDP-43 mice as a better control than the non-transgenic mice utilized in this study. So although clearly not all is answered yet, let's see how these and other TDP-43 mouse models currently being developed will unfold the mysteries of TDP-43-led neurodegeneration.
View all comments by Samir Kumar-Singh |
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Related News: Another Screen, Another Gene: ALS and the Right-handed Serine
Comment by: Steve Barger
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Submitted 27 April 2010
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Posted 29 April 2010
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Regarding the statement in this news story "De Belleroche also pointed out that a DAO mutant mouse might be a useful model for ALS research, which sorely needs new models," I'd like to note that it is unlikely that loss of DAO alone will be sufficient for disease. A line of DAO mutant mice, essentially devoid of DAO activity, has been around almost 30 years (Konno and Yakumura, 1983) without any ALS-like symptoms reported in the first year of life. Here is a quote from that paper:
"No apparent difference was detected between DAO+ and DAO- mice. The DAO- mice grew and behaved normally. They were fertile and produced as many offspring as the DAO+ animals did. Besides, the unilaterally nephrectomized DAO- mice lived more than 1 year without any impairment of health. ...[T]he discovery of the DAO- mice suggests that the enzyme is not essential, at least for the growth and reproduction of the mouse under laboratory conditions."
References:
Konno R, Yasumura Y. 1983. Mouse mutant deficient in D-amino acid oxidase activity. Genetics 103:277-85. Abstract
View all comments by Steve Barger |
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