Neurons possess extensive tubulin post-translational modifications (PTMs) that are associated with microtubule (MT) longevity, and analyses of mammalian brain and cultured neurons demonstrate enrichment of detyrosinated, acetylated, poly-glutamylated and D2-tubulin subunits. These tubulin PTMs are implicated in the regulation of MT associated proteins (known as MAPs), MT severing enzymes, and binding to motors.
Synaptic activation also locally regulates tubulin PTMs associated with MT stability. In addition to stable MTs, emerging studies indicate that dynamic MTs, typically deprived of tubulin PTMs, play key roles in neuronal function. Dynamic MTs polymerize from dendritic shafts into spines, and signaling through neurotransmitter receptors and local calcium entry regulate this process. Invasion of dendritic spines by dynamic MTs can in return affect spine morphology and function by regulating myosin- and kinesin-paired cargo dynamics. Furthermore, presynaptic dynamic MTs are necessary for the delivery of synaptic vesicles to their appropriate sites, and may mediate storage and/or docking /fusion of vesicles at the active zone.
Thus, aside from their more conventional role in offering structural support to the neuron, MTs are fine regulators of neuronal homeostasis and synaptic function, and unwanted changes in MT dynamics, stability and/or tubulin PTMs may be involved in the onset of neurodegenerative and neuropathic disease. To tackle these questions, my lab employs biochemical and cell-biological approaches using immortalized non-neuronal cells, primary neuronal cultures and animal models of disease.
Role of tubulin PTMs in organelle contacts
This project aims at deciphering the role of tubulin modifications in organelle contacts
Formin-mediated Microtubule Hyperstabilization in Amyloid-beta Synaptotoxicity
We are testing the hypothesis that formin function is required for amyloid beta synaptotoxicity in animal and cellular models of AD
Pathogenic role of tubulin PTMs in neurodegenerative and neuropathic disease
This project aims at identifying whether disturbances in tubulin modifying cycles may drive neurodegeneration and neuropathic disease
•To employ state-of-the art cell biology approaches to get us closer to decipher the mechanisms underlying neurodegenerative disease
•To share information and provide an avenue of how basic cell biology translates into impact on neurodegenerative disease and more broadly to the onset of other types of neuronal injuries like motor neuron disease and peripheral neuropathies
•To provide a stimulating opportunity for students and post-doctoral fellows to build cross-cutting collaborations that could lead to breakthroughs in the field
Characterization of the microtubule cytoskeleton at synapses
This project aims at revealing unexplored functions of the microtubule cytoskeleton at synapses