BRUCE H. MORIMOTO*, ALISTAIR J. STEWART
*Corresponding author
Allon Therapeutics Inc. 1168 Hamilton Street, Suite 506 Vancouver, British Columbia, V6B 2S2 Canada

Abstract

Microtubule (MT) destabilization is common to many neurodegenerative diseases including Alzheimer’s disease and Progressive Supranuclear Palsy (PSP) where MT dysfunction leads to the development of characteristic tau pathology associated with aggregation of the MT-associated protein, tau. Functional MTs are responsible for retrograde transport and therefore also play a key role in autophagy and the clearance of protein inclusions. In addition to these roles attributed to MT in axons, MTs are involved in the regulation of the post-synaptic, dendritic spine structures. Therefore, therapeutic intervention leading to the repair of dysfunctional MTs has the potential to not only confer neuroprotection, but also improve synaptic communication. Davunetide is a peptide therapeutic in which the neuroprotectant activity appears to be mediated by MT stabilization, and has the potential to treat several CNS disorders involving MT dysfunction including PSP.

INTRODUCTION

Microtubules (MTs) are critical for the proper structure and function of neurons. MTs are dynamic and polarized structures consisting of aaand a tubulin dimers which polymerize end-to-end thereby giving a (+) and (-) end with elongation occurring at the (+) end. Dynamic instability is a property of MTs which refers to the simultaneous assembly and disassembly at the (+) end. This allows MTs to rapidly switch between growth and retraction. The dynamic behaviour of MTs is critical for proper function and can be regulated by various microtubule-associated proteins (MAP), MT motor proteins (kinesin & dynein) and MT severing proteins (spastin & katanin).
Dynamic MTs require cellular energy. The addition of TT tubulin dimers to the growing MT involves GTP hydrolysis. Therefore, under conditions of energy stress, the ratio of GDP-tubulin to GTP-tubulin would increase, leading to a net destabilized cytoskeleton. Hoglinger and colleagues hypothesize that mitochondrial dysfunction which leads to ATP depletion results in a cascade of events leading to MT destabilization and tau pathology (1). The link between mitochondrial impairment, r ...