Loss of Dynein in Mice Linked to Late-Onset Neuromuscular Disease in Humans

Newswise — Human suffering can seem remote from the molecular hurly-burly inside living cells. However, a new discovery about neuronal transport in mice may clarify a rare but devastating progressive neuromuscular disease in humans.

In work presented at the American Society for Cell Biology's 43rd Annual Meeting in San Francisco, Erika Holzbaur and colleagues at the University of Pennsylvania Medical School describe how they created transgenic mice whose motor neurons had a defect in retrograde transport, that is, the ability to move material in nerve axons back toward the nucleus. They specifically disrupted the function of a molecular motor named dynein. Activated by a protein complex called dynactin, dynein is a one-way motor that uses microtubules as tracks to return cargo from the distal (far) end of axons to the main cell body. In human motor neurons, these microtubule highways can be a meter long, and transport in both directions is vital for nerves to resupply axons and communicate with the neuromuscular junctions.

The loss of dynein disrupted retrograde transport. Unexpectedly, Holzbaur's mice slowly developed signs of late-onset, progressive motor neuron disease. Direct examination revealed a trio of problems: the accumulation of neurofilaments, defects in neuromuscular junctions and loss of motor neurons.

This pattern of symptoms clicked with Kurt Fischbeck at NIH's National Institute of Neurological Disorders and Stroke (NINDS) who had genetic data from a North American family with a remarkably similar disease phenotype. Family members develop an autosomal dominant, lower motor neuron disease characterized by breathing difficulties, facial weakness, and muscle atrophy in the hands, and later the legs.

Together, members of the Holzbaur and Fischbeck labs found a link between the engineered mice and this family. Members of this family carry a defective gene encoding one subunit of dynactin, which activates dynein. Their mutation alters a highly-conserved structural motif in dynactin, disrupting its activity and possibly leading to misfolding of the protein, says Holzbaur. This unexpected connection could have implications for other progressive neuromuscular diseases such as ALS (amyotrophic lateral sclerosis).

Disruption of retrograde axonal transport causes motor neuron disease in both humans and mice, Bernadette LaMonte, Karen Wallace, and Erika L. F. Holzbaur, University of Pennsylvania School of Medicine. Funding: Supported by the ALS Association, and NIH grants GM48661 and GM56707. BLM is supported by the training grant NIH AR07584.