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

By M. Hafezparast, R. Klocke, C. Ruhrberg, A. Marquardt, A. Ahmad-Annuar, S. Bowen, G. Lalli, Abi S. Witherden, H. Hummerich, Sharon J. Nicholson and 29 more. Science, 2003

739 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/023595baed874baa6fcb4b75204ced14193947de

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. Yosuke Tanaka
2. Shinsuke Niwa
3. M. Coleman
4. N. Hirokawa
5. D. Rubinsztein
6. Debashish Chowdhury

In Genetics

1. Shinsuke Niwa
2. Yosuke Tanaka
3. Robert H. Brown
4. N. Hirokawa
5. P. Pasinelli

In Neurology

1. Robert H. Brown
2. P. Pasinelli
3. D. Rubinsztein

Citations in the corpus

• Axon degeneration mechanisms: commonality amid diversity (2005, background): “, whereas defects in retrograde transport also cause cell body deat”
• The roles of intracellular protein-degradation pathways in neurodegeneration (2006, background): “, and dynein heavy-chain mutations in the legs at odd angles ( Loa ) and cramping ( Cra1 ) mice”
• Molecular biology of amyotrophic lateral sclerosis: insights from genetics (2006, background): “In two lines of mice (legs at odd angles and cramping), point mutations in the dynein heavy chain impair motor neuron function and viabilit”
• Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. (2010, positive): “Allelic point mutations of the cytoplasmic dynein heavy chain 1 were identified in the Loa and Cra1 mouse strains, causing late-onset motor neuron degeneration in heterozygotes and neuronal apoptosis in homozygotes (Hafezparast et al., 2003).”
• Non-commercial Research and Educational Use including without Limitation Use in Instruction at Your Institution, Sending It to Specific Colleagues That You Know, and Providing a Copy to Your Institution's Administrator. All Other Uses, Reproduction and Distribution, including without Limitation Comm (2005, neutral): “For solutes with more spins and less symmetry, the number of different dipole–dipole interactions increases rapidly, thus making the analysis of complex NMR spectra notoriously difficult.”
• Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. (2004, background): “We observed a statistically significant increased cell death in 109Q/109Q cells in transport inhibition and neurodegeneration in mouse (Burkhardt et al., 1997; Hafezparast et al., 2003; LaMontecomparison to / cells (Figure 7G).”