Microtubule Defects and Neurodegeneration

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.

Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimers Disease and Related Tauopathies

“…Neurons are particularly vulnerable to dysfunction resulting from MT instability, because they rely on MT networks both for architectural support and for the axonal transport of critical cellular proteins and organelles (Alonso et al, 1997;Baird and Bennett, 2013). Thus, the loss of tau function would be predicted to be detrimental to MT function and neuronal health, as supported by the aforementioned observations in the AD brain.…”

Microtubule and microtubule associated protein anomalies in psychiatric disease

“…Clinically relevant evidence for altered a-tubulin modifications in postmortem brain from patients with Alzheimer's [Zhang et al, 2015] Huntington's and Parkinson's disease [Perdiz et al, 2011] have also been reported, however the involvement of the microtubule cytoskeleton in the molecular mechanisms of neurodegenerative diseases has been extensively reviewed elsewhere [McMurray, 2000;Lingor et al, 2012;Baird and Bennett, 2013].…”

Protein post‐translational modifications and misfolding: New concepts in heart failure

“…In the brain, the protein tau is a member of microtubule‐associated proteins (MAPs) and its hyperphosphorylated form is a well‐established component of neurofibrillary tangles in AD (reviewed in ). A role for Tyr nitration was postulated in the formation of tau aggregates whereas a link between deamidation and isomerization of tau and the formation of aggregates has not been established although these PTMs have also been reported .…”