In today’s Science, researchers report that mutations in the protein dynein-the motor that drives the transport of large molecules from the synaptic terminal back to the neuron’s cell body-can lead to forms of neurodegeneration reminiscent of motor neuron diseases such as amyotrophic lateral sclerosis (ALS).
This is not the first evidence implicating axonal transport in neurodegenerative disease. Loss or interference with the protein dynactin, a component of the motor complex, has previously been shown to result in poor retrograde transport and the complete loss of axons in mice (see ARF related news story).
Axonal transport is also implicated in Alzheimer’s (see ARF related news story; also ARF story). Now, a multinational collaboration led by Elizabeth Fisher at the National Hospital for Neurology and Neurosurgery in London, U.K., reports that Legs at odd angles (Loa) and Cramping 1 (Cra1), two chemically-induced mutations that cause progressive loss of locomotor function, are actually point mutations in the heavy chain of cytoplasmic dynein-the Loa mutation being a change from phenylalanine at position 580 to tyrosine, while Cra1 results from a tyrosine-to-cysteine switch at position 1,055 of the protein.
Joint first authors Majid Hafezparast and Rainer Klocke characterized these two mutations and found that dynein levels are unaltered in both homozygous and heterozygous animals as compared to wild-type controls. The authors also found that the Golgi apparatus, a subcellular production line for protein modification and maturation that relies on dynein for protein conveyance, appeared normal in Loa homozygotes. However, when nocodazole was used to disrupt the apparatus, its reassembly was compromised in Loa mice. It is worth noting that in human ALS, the Golgi apparatus has been reported to be extensively fragmented, much like in nocodazole-treated cells.
Hafezparast and colleagues also found that motor neurons, especially those controlling facial muscles, fail to develop normally in Loa mutants. This is significant because facial motor weakness is a hallmark of spinal-bulbar muscular atrophy and some subtypes of ALS. To discover if axonal transport is compromised in these mutants, the authors visualized retrograde axonal transport using a fragment of tetanus toxin as a fluorescent marker. When Hafezparast and Klocke added the tetanus fragment to motor neurons cultured from Loa mutants, they found that retrograde transport was significantly slower than in control neurons. For example, the number of tetanus fragments moving along the axons at high speed was reduced to less than half, while the number of fragments that appeared to be stationary was more than doubled. Because dynein is involved in many other cellular processes, such as cell division, the latter results are key to linking dynein activity, retrograde transport, and loss of neuronal function.
Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, de Angelis MH, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE, Fisher EMC. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003 May 2;300:808-812. Abstract
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