Probing microtubule organisation
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Microtubules, cytoskeletal polymers of tubulin, are critical contributors to normal brain development and maintenance. Across a spectrum of neurodegenerative conditions including Parkinson’s and Alzheimer’s disease, microtubule functions are dysregulated, and mutant microtubule and/or their regulatory microtubule-associated proteins result in severe brain developmental defects, intellectual disability and epilepsy. Despite this clear significance, large gaps remain in our understanding of how MAPs are regulated and how disease-causing mutations impact on their actions. In this project, our focus is Doublecortin X-linked (DCX); the importance of DCX is highlighted by clinical studies showing multiple different DCX gene mutations as the cause of a disease spectrum typified by epilepsy, seizures, and intellectual disability arising from abnormal neuron migration during development and the disruption of the layering of the brain cortex. At a biochemical level, DCX interacts with microtubules via its structured DC domains. Although clustering of pathogenic mutations in the DC domain has strengthens a hypothesis that defects in DCX-microtubule interactions underlie brain developmental defects, many pathogenic DCX mutants continue to associate with microtubules, highlighting the need to explore additional regulatory defects. Indeed, some pathogenic mutations lie outside the DC domains. Our studies exploring the impact of truncated forms of DCX, pathogenic DCX mutations lying outside the DC domains and a novel N-terminal phosphorylation site have reinforced the importance of regions outside the DC domains. We are now evaluating how DCX actions can be controlled by its N- and C-termini to direct appropriate spatial and temporal control of microtubule organisation. Key methodologies used in these projects range from high resolution and live imaging in cells to focused structural and biochemical studies.
Dr Dominic Ng, University of Queensland
Associate Professor Paul Gooley, Bio21
Professor Staffan Persson, University of Melbourne Biosciences
Professor Carolyn Moores, UK
Professor Attila Remenyi, Hungary
- Yip YY, Yeap YY, Bogoyevitch MA, Ng DC. cAMP-dependent protein kinase and c-Jun N-terminal kinase mediate stathmin phosphorylation for the maintenance of interphase microtubules during osmotic stress. J Biol Chem 2014;289(4): 2157-69.
- Zeke A, Misheva M, Remenyi A, Bogoyevitch MA. JNK signaling: regulation and functions based on complex protein-protein partnerships. Mol Microbiol Reviews 2016 in press.
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