Abstract
One of the major challenges facing the long term survival of neurons is their requirement to maintain efficient axonal transport over long distances. In humans as large, long-lived vertebrates, the machinery maintaining neuronal transport must remain efficient despite the slow accumulation of cell damage during aging. Mutations in genes encoding proteins which function in the transport system feature prominently in neurologic disorders. Genes known to cause such disorders and showing traditional Mendelian inheritance have been more readily identified. It has been more difficult, however, to isolate factors underlying the complex genetics contributing to the more common idiopathic forms of neurodegenerative disease. At the heart of neuronal transport is the rail network or scaffolding provided by neuron specific microtubules (MTs). The importance of MT dynamics and stability is underscored by the critical role tau protein plays in MT-associated stabilization versus the dysfunction seen in Alzheimer's disease, frontotemporal dementia and other tauopathies. Another example of the requirement for tight regulation of MT dynamics is the need to maintain balanced levels of post-translational modification of key MT building-blocks such as α-tubulin. Tubulins require extensive polyglutamylation at their carboxyl-terminus as part of a novel post-translational modification mechanism to signal MT growth versus destabilization. Dramatically, knock-out of a gene encoding a deglutamylation family member causes an extremely rapid cell death of Purkinje cells in the ataxic mouse model, pcd. This review will examine a range of neurodegenerative conditions where current molecular understanding points to defects in the stability of MTs and axonal transport to emphasize the central role of MTs in neuron survival.
Highlights
The focus of this review will be the role of Microtubule (MT) stabilization and axonal transport as they relate to human pathology by looking at a series of inherited and sporadic conditions defined by neurodegeneration
In this review we have focused on the microtubule and some of its important component building blocks such as α-tubulin and the stabilizing role played by microtubule-associated proteins (MAPs) proteins such as tau
Our goal here was to draw together an overview of a range of primarily inherited disorders, where the mutations likely have a direct bearing on MT function within the neuron
Summary
Fiona J Baird and Craig L Bennett1,3* 1School of Pharmacy and Molecular Sciences, James Cook University, DB 21, James Cook Drive, Townsville, QLD 4811, Australia 2Centre of Biodiscovery and Molecular Therapeutics, James Cook University, DB 21, James Cook Drive, Townsville, QLD 4811, Australia 3Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
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