Identification of a new mode of regulation of axonal transport
Laurent Nguyen's laboratory (GIGA-Stem Cells and GIGA-Neurosciences, University of Liège) continues to make progress in understanding the axonal transport process, which is lacking in many neurodegenerative diseases.
he axon (or nerve fibre) corresponds to the extension of the neuron and conducts electrical information from the cell body to the synapse. It comprises a network of microtubules that serve as "rails" on which molecular motors transport many molecules (axonal transport) from the cell body to the synapse and vice versa, in order to ensure neuronal maturation and later survival. Many neurodegenerative diseases (such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis) are characterized by axonal transport defects. In order to better understand these diseases, it is thus necessary to determine the mechanisms underlying this process in nerve fibres. For optimal axonal transport, microtubules are subject to modifications, such as acetylation for example (post-translational modifications) by enzymes that control and adapt transport speed.
It is in this context that Laurent Nguyen's team (Laboratory of molecular regulation of neurogenesis) discovered a non-canonic function of axonal vesicles (membrane bags containing the molecules to be transported). These soft vesicles move in axons along microtubules and are enriched with ATAT1 enzymes that regulate the acetylation of microtubules. Their results have just been published in Science Advances.
GIGA researchers show in this publication that there is a positive feedback loop through which axonal vesicles containing the enzyme ATAT1 promote the transport of the vesicles that will follow by acetylating the microtubules. The acetylation of microtubules therefore corresponds to a regulatory process crucial for the proper functioning of the neuron during its development, maturation but also to ensure its survival.
This discovery will provide a better understanding of axonal transport disorders that occur in neurodegenerative diseases. It is therefore possible to consider, in the long term, acting directly on axonal transport, with pharmacological molecules that would modify the activity of enzymes that regulate, in a positive or negative way, the acetylation of microtubules.
Super-resolution microscope image of a human neuron derived from pluripotent stem cells illustrating the enrichment of the ATAT1 enzyme (red) in the axonal synaptic vesicles (Synaptophysin, green).
ATAT1-enriched vesicles promote microtubule acetylation via axonal transport
Aviel Even1*, Giovanni Morelli2,3*, Loïc Broix2*, Chiara Scaramuzzino4,5, Silvia Turchetto2, Ivan Gladwyn-Ng2, Romain Le Bail2, Michal Shilian1, Stephen Freeman2, Maria M. Magiera6,7, A. S. Jijumon6,7, Nathalie Krusy2, Brigitte Malgrange2, Bert Brone3,8, Paula Dietrich9, Ioannis Dragatsis9, Carsten Janke6,7, Frédéric Saudou4,5,10, Miguel Weil1*†, Laurent Nguyen2*†
Science Advances (2019)
On the first picture : Loïc Broix, Silvia Turchetto et Laurent Nguyen
Dr Laurent Nguyen
Laboratoire de la Régulation Moléculaire de la Neurogenèse, GIGA-Stem Cells et GIGA-Neurosciences
Tel +32 4 366 59 87