Mouse models for neurological disease

Hafezparast, Majid; Ahmad‐Annuar, Azlina; Wood, Nicholas W.; Tabrizi, Sarah J.; Fisher, Elizabeth

doi:10.1016/s1474-4422(02)00100-x

Cited by 44 publications

(47 citation statements)

References 125 publications

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“…Dynein function is regulated by another multisubunit protein, dynactin, which through its p150 subunit also plays a significant role as a docking protein for some of the various cargos transported by dynein (30). We have previously shown that an autosomal dominant point mutation causing F580Y substitution in DHC gives rise to a progressive motor deficit in heterozygous Loa ( Dync1h1 Loa /+ ) mice (31–33) and that in cultured motor neurons isolated from E13.5 homozygous embryos this mutation impairs retrograde axonal transport leading to motor neuron degeneration and death of the pups within a day after birth (31). In addition, others have shown that the Loa mutation causes γ-motor neuron and proprioceptive sensory neuron degeneration in heterozygous Dync1h1 Loa /+ which is thought to be the cause of the phenotype in these mice (34, 35).…”

Section: Introductionmentioning

confidence: 99%

The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease

El-Kadi

Bros-Facer²,

Deng

et al. 2010

Journal of Biological Chemistry

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Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute ∼10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15–20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1G93A. In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1G93A motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1G93A motor neurons.

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Section: Introductionmentioning

confidence: 99%

The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease

El-Kadi

Bros-Facer²,

Deng

et al. 2010

Journal of Biological Chemistry

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“…Hundreds of different genes expressed in the central nervous system have been targeted in transgenic and knockout mice (Hafezparast et al, 2002;Watase and Zoghbi, 2003). Comparison of the mouse and human brain transcriptomes shows a good correlation for highly expressed genes in both transcript identity and abundance (Fougerousse et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Systematic, standardized and comprehensive neurological phenotyping of inbred mice strains in the German Mouse Clinic

Schneider

Tirsch²,

Faus-Keßler

et al. 2006

Journal of Neuroscience Methods

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“…12 This is particularly useful when looking at mechanisms and pathways of cell death, since it is not possible to look at this systematically in human patients. Phenotypic data can then be combined with molecular analyses, such as from microarray experiments with brain/ nervous system cDNAs, or proteomics approaches, to pinpoint aberrant pathways and cellular deficits (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles because we share a common ancestor and therefore common genomes. 12 The recent publication of the draft mouse genome sequence has 13 confirmed the high degree of homology between mouse and human, and has added considerably to the genetic resources available for the mouse. Clearly there are physiological differences, not least in size and life-span, and these will have some effect on the manifestation of DNA mutations at the level of the organism.…”

Section: Introductionmentioning

confidence: 99%

Paradigms for the identification of new genes in motor neuron degeneration

Hafezparast

Ahmad‐Annuar

Hummerich

et al. 2003

Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders

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It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).

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Mouse models for neurological disease

Cited by 44 publications

References 125 publications

The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease

The Legs at odd angles (Loa) Mutation in Cytoplasmic Dynein Ameliorates Mitochondrial Function in SOD1G93A Mouse Model for Motor Neuron Disease

Systematic, standardized and comprehensive neurological phenotyping of inbred mice strains in the German Mouse Clinic

Paradigms for the identification of new genes in motor neuron degeneration

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