Cytoskeleton club - Magda Magiera

Speaker: Magda Magiera - Genome Integrity, RNA and Cancer (UMR3348), Curie Institute, Orsay

Title: Microtubule polyglutamylation is a key player in neuronal homeostasis and causes neurodegeneration if dysregulated

Abstract: I will talk about tubulin polyglutamylation, a posttranslational modification of microtubules, and its role in neuronal function and homeostasis. Microtubules are present in every eukaryotic cell where they exert a wide variety of functions. This functional diversity requires a continuous readjustment of microtubule functions, especially in highly differentiated, complex and long-lived cells such as neurons. We have shown that polyglutamylation, a prominent tubulin modification of neuronal microtubules, can cause neurodegeneration when upregulated, both in humans and in a mouse model closely replicating the human disease. Moreover, our recent results revealed that reduced levels of polyglutamylation also lead to degenerative phenotypes. Together these two findings highlight the importance of tightly controlled levels of this modification for neuronal survival. On the cellular level, polyglutamylation regulates axonal transport: increased polyglutamylation down-regulates cargo traffic, while reduced levels of this modification have an inverse effect. To decipher underlying molecular mechanisms, we developed a medium-throughput approach to measure how polyglutamylation affects the interactions of a broad range of microtubule-associated proteins, which showed that neuronal MAPs are sensitive to this modification. We are currently exploring the effects of these perturbations on cellular functions such as autophagy, neuronal activity and other aspects of neuronal physiology. I will also discuss how polyglutamylation, by controlling the behaviour of the microtubule-associated protein tau, could be involved in human late-onset neurodegenerative disorders.