Trends in Cell Biology
Volume 14, Issue 5, 1 May 2004, Pages 233-240
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Motor neurons rely on motor proteins

https://doi.org/10.1016/j.tcb.2004.03.009Get rights and content

Abstract

The importance of active axonal transport to the neuron has been highlighted by the recent discoveries that mutations in microtubule motor proteins result in neurodegenerative diseases. Mutations affecting microtubule motor function have been shown to cause hereditary forms of Charcot–Marie-Tooth disease (type 2A), hereditary spastic paraplegia and motor neuron disease. Although motor neurons appear to be uniquely susceptible to defects in axonal transport, recent work has identified links between perturbations in axonal transport and the pathogenesis of other neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. More broadly, cytoskeletal abnormalities might also be at the root of related disorders such as spinal muscular atrophy, supporting a key role for axonal transport in the pathogenesis of many neurodegenerative diseases.

Section snippets

Kinesins

Initial observations in invertebrate models clearly showed the crucial role of kinesin during the development of the nervous system [3]. Although major defects in the organization of the neuromuscular system are not observed in Drosophila expressing mutations in kinesin heavy chain, at the cellular level axons develop marked swellings packed with vesicles, synaptic membrane proteins and mitochondria. Dystrophic neuromuscular junctions were also observed [4]. Mouse knockouts of two of the three

Interdependency of microtubule motors

Axonal transport is bidirectional, and accumulating evidence suggests that anterograde and retrograde motors function in an interdependent manner. Antibodies to either kinesin or dynactin result in a bidirectional inhibition of transport of vesicular motility in axoplasm in vitro 25, 26, 27. In Drosophila, dominant genetic interactions have been noted among kinesin, cytoplasmic dynein and dynactin [28]. We have observed a direct biochemical interaction between kinesin and cytoplasmic dynein

Transport defects linked to motor neuron degeneration

Although it is not surprising that microtubule motor proteins are required for the complex cytoskeletal changes occurring as neurons differentiate, migrate, extend growth cones and establish appropriate synaptic connections during development, the ongoing function of mature neurons is also dependent on active transport. This transport might be essential to maintain the health of all neurons but becomes particularly key in cells with extended axons such as those of the peripheral nervous system.

Is transport the Achilles' heal of the neuron?

If neurons are particularly dependent on axonal transport then both direct and indirect inhibition of this transport might be either causative or contributory factors to neurodegenerative disease. Although direct inhibition might be due to the types of motor mutations described above and summarized in Table 1, indirect effects might include the slowing of transport by protein aggregates or cytoskeletal disorder. For example, as described above, the accumulation of neurofilaments in the axon of

Concluding remarks and outstanding questions

Progress in understanding the mechanisms that drive axonal transport has been steady since the discovery of the intracellular microtubule motors kinesin and cytoplasmic dynein. These motors clearly play a role in the normal development of the nervous system, affecting neuronal migration, axonal pathfinding and synapse stabilization. However, studies of neurodegenerative diseases have highlighted the role of active axonal transport in maintaining the continued health of neuronal cells with

Acknowledgements

I thank Lee Ligon, Kevin K. Pfister, Karen Wallace, Mariko Tokito and David Howland for their intellectual input. I also thank Lee Ligon and the laboratories of Nobutaka Hirokawa, Larry Goldstein, Elizabeth Fisher and Gabriele Strumm for providing figures. My work was supported by a National Institutes of Health grant (GM48661) and the ALS Association.

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