Is reduced cytoplasmic dynein function a cause and a risk factor of MND?
Why motor neurons die in ALS remains unknown. Motor neurons possess a very long extension, the axon, that enables them to contact muscle and control its movement. In axons, an intricate trafficking of cellular components occurs from the cell body of the motor neuron to the site of contact with the muscle (anterograde direction), and the other way round (retrograde direction). It has long been thought that defects of transport in the axon might underlie degeneration of motor neurons, especially for retrograde axonal transport. This is supported by the existence of changes in the dynein proteins, that are the molecular motors responsible for retrograde axonal transport, in rare cases of familial ALS. However, it remains unclear whether and how reduced dynein function can cause on its own, or facilitate, motor neuron disease. In this project, we generate mice with different levels of the dynein protein in motor neurons to study whether this provokes the disease. In parallel, we can determine whether mildly reducing dynein is able to exacerbate the degeneration of motor neurons in a mouse model with a mutation in an ALS-associated gene known as Fused in sarcoma (FUS). Moreover, we want to establish whether loss of dynein leads to abnormal accumulation of proteins found in brains of ALS patients. The completion of this project will help us to understand the role of dynein in ALS, and whether this enzyme should be targeted for future therapeutics.
Hafezparast M, et al., Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003, 300:808-12.