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Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport

Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport,10.1126/science.1083129,Science,Majid Hafezparast,Rainer Klocke,

Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport   (Citations: 239)
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Majid Hafezparast, Rainer Klocke, Christiana Ruhrberg, Andreas Marquardt, Azlina Ahmad-Annuar, Samantha Bowen, Giovanna Lalli, Abi S. Witherden, Holger Hummerich, Sharon Nicholson, P. Jeffrey Morgan, Ravi Oozageerhttp://academic.research.microsoft.com/io.ashx?type=5&id=4130749&selfId1=0&selfId2=0&maxNumber=12&query=
Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.
Journal: Science , vol. 300, no. 5620, pp. 808-812, 2003
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    • ... It decreases the rate of retrograde axonal transport and contributes to sensory and/or motor neuron degeneratio...

    Richard J. McKenneyet al. Multiple modes of cytoplasmic dynein regulation

    • ...Three different mutations in the dynein heavy chain gene, respectively called “legs at odd angles“ (Loa), “Cramping“ (Cra) and “Sprawling“ (Swl) have been identified in ENU-induced mouse strains [9,10]...
    • ...Indeed, dynein mutant mice were initially thought to develop motor neuron degeneration [9], and it appeared difficult to understand how mutating dynein, and thus precipitating late onset motor neuron degeneration, might protect against early onset SOD1(G93A)-mediated neurodegeneration...
    • ...Animals Heterozygous Cra/+ females were crossed with SOD93A males and were identified by tail DNA genotyping for the human transgene SOD1 (G93A) and the Cra mutation as described previously [7,9]...

    Anissa Ferganiet al. A mutation in the dynein heavy chain gene compensates for energy defic...

    • ...In contrast to SOD1 mice, the life span of Cra1 and Loa heterozygotes remains almost unchanged compared to wild-type animals [8]...

    Magdalena Kuźma-Kozakiewiczet al. Mice with Mutation in Dynein Heavy Chain 1 Do Not Share the Same Tau E...

    • ...However, several dynein mutant mouse strains have since been identified in screens for genes involved in neurodegeneration [18,19]...
    • ...The Loa heterozygous mice are viable and develop early onset neurodegenerative disease, but the homozygous animals die perinatally due to an inability to feed [18]...
    • ...Interestingly, both the Loa/+ and the Loa/Loa mice exhibited defects in retrograde axonal transport [18,22]...
    • ...The Loa/Loa mice have been reported to display abnormal facial motor neuron organization, suggesting potential cellular migration defects [18]...

    Kassandra M Ori-McKenneyet al. Neuronal migration defects in the Loa dynein mutant mouse

    • ...Gene expression was evaluated at two distinct ages: 55 and 110 days, representing presymptomatic and full-blown disease statuses in G93A mice, respectively (Crochemore et al. 2005; Gurney 1994; Rowland 2000)...
    • ...Transgenic mice expressing a high copy number of the wild-type or mutated G93A human SOD1 gene (glycine/ alanine substitution at codon 93) were used (Gurney 1994)...
    • ...Mice with high copy number of mutated human SOD1 with the G93A substitution have been mostly used as they closely recapitulate symptoms and progression of the human disease (Gurney 1994)...
    • ...They develop paralysis symptoms by 3 months of age, undergo sizable motor neuron degeneration in the lumbar and cervical spinal cord by 100–115 days of age and show rapid disease progression with death occurring around 135 days of age (Crochemore et al. 2005; Gurney 1994; Rowland 2000)...

    Antonello D’Arrigoet al. Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model o...

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