In yesterday’s Neuron, researchers show that disruption of axonal transport systems in transgenic mice leads to a late-onset, slowly progressive motor neuron disease reminiscent of those human motor neuron diseases. A major impediment to developing therapeutics for amyotrophic lateral sclerosis (ALS) and related motoneuron diseases is that the molecular basis for the neuronal damage remains poorly understood. Some familiar cases of ALS are related to mutations in the copper/zinc superoxide dismutase (SOD) gene, but exactly how this affects neurons is still uncertain. One theory holds that mutant SOD restricts transport along neuronal axons. Indeed, scientists have been looking more and more to these essential transport systems-which carry proteins as far as several feet from the cell body to the tip of the axon-to find clues to the etiology of ALS. (See ARF news item on axonal transport in AD.)
Erika Holzbaur and colleagues at the University of Pennsylvania in Philadelphia and Wyeth Research in Princeton, New Jersey, overexpressed the protein dynamitin in transgenic mice. Dynamitin throws a spanner in the transport works by disrupting the dynactin protein complex. Dynactin acts like an alternator. Without it, the motor protein dynein, which drives the transport of neurofilaments along axons, cannot function. The researchers engineered the mice to begin expressing dynamitin about two weeks after birth, as functional dynein is essential for development.
The transgenic mice appeared normal until they were about 5 to 9 months old, whereupon they began to show symptoms of motor neuron loss, including awkward gait, poor locomotion, weakness, and atrophy of the skeletal muscles. These symptoms correlated with dynactin disruption and with accumulation of neurofilaments in the axons. Furthermore, mice with late symptomatic signs of neuron disease (>16 months old) had lost about 25 percent of their axons. Those with intermediate-stage symptoms exhibited dramatically poorer retrograde transport from the nerve terminal to the cell body, exactly the type of defect that would be expected if dynein function was compromised.
Meanwhile, in the same issue of Neuron, researchers in Graeme Davis’ lab at University of California, San Francisco, report that in Drosophila, dynactin is also essential for stabilizing synapses at the neuromuscular junction. The making and breaking of these synapses, or synapse remodeling, is known to be essential during development and also later in life, as it facilitates the rewiring that is essential for activity-based learning.
Davis et al. devised an assay to measure retreating synapses based on a protein footprint they left in the muscle. The Discs-large protein, for example, is recruited to the muscle side of the neuromuscular junction; its presence in the absence of neural markers indicates a retracted synapse.
Using this assay, the authors found that several proteins that contribute to the dynactin complex, including Arp-1 and Glued-1, are essential for maintening these synapses. Inhibiting the expression of Arp-1 by RNA interference, or expressing dominant-negative mutants of Glued-1, increased the frequency and extent of synaptic retraction. Not all synapses retract, however, and the cells otherwise seemed healthy. It would be interesting to apply this retraction assay to mammalian models of dynactin dysfunction.
LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, Van Winkle T, Howland DS, Holzbaur ELF. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron. 30 May 2002;(34):715-727. Abstract
Eaton BA, Fetter RD, Davis GW. Dynactin is necessary for synapse stabilization. Neuron. 30 May 2002;(34):729-741. Abstract
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