Francesca Bartolini, PhD

Cells possess both stable and dynamic microtubules composed of the polarized addition of a-and b-tubulin subunits. Dynamic microtubules differ from stable microtubules in their ability to undergo stochastic transitions between their polymerization and depolymerization states. Stable microtubules, conversely, resist depolymerization and are decorated by several tubulin post-translational modifications (PTMs). The combinatorial nature of these covalent modifications gives rise to a “tubulin code”, a molecular mechanism to coordinate complex cellular functions by regulating the binding of microtubules to motors and MAPs, microtubule severing, channel permeability and organelle-organelle contacts.

Despite these fundamental findings, it is unknown if anomalies in the balance between stable and dynamic microtubules are a feature of neurological disease. Whether microtubules play a direct role in the machinery that regulates synaptic transmission and plasticity is similarly understudied. Finally, whether microtubules act as a hub for the convergence of signals coordinating microtubule associated proteins, motor activity and organelle/organelle communication is largely unexplored.

The overarching goal of our research is to decipher the role of microtubule dynamics and tubulin modifications in synaptic plasticity and neurological disease. Our work is anchored in examining microtubule and tubulin biology in synapses and neuronal compartments using cellular and mouse models of CNS and PNS disease and has recently expanded into decoding these changes in primary glia cells, human cortical neurons reprogrammed from iPS isogenic cell lines carrying disease mutations, and in the acute brain slice.

By combining tubulin biochemistry and microtubule biology with molecular andbehavioral neuroscience in animal models of disease, my lab is uniquely positioned to work at the interface of cell biology and the pathophysiology of neurodegenerative and neuropathic disease.My current projects can be summarized in three major areas:

1) The “tubulin code” in neurodegeneration. Our observations suggest that activators of tubulin re-tyrosination may be beneficial for restoring circuit integrity in sporadic and familial Alzheimer’s disease. The molecular factors associated with the resistance of dynamic microtubules-invaded spines however remain to be identified. Our future studies are designed to provide mechanistic evidence for how inhibition of tubulin re-tyrosination affects synaptic microtubule dynamics and acts as a molecular driver of tau hyperphosphorylation.

2) The “tubulin code” in peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN). Our studies are designed to evaluate whether CIPN-promoting drugs may share an underlying mechanism of pathogenesis based on modulation of one or more tubulin PTMs during a prodromal stage of the disease. We further wish to examine whether accumulation of D2 tubulin in sensory neurons, which we have observed to occur in several classes of chemotherapeutic drugs, plays a common pathogenic role in neuropathic damage by contributing to mitochondrial and TRP channel dysfunction. Charcot-Marie-Tooth disease. Tubulin is the only known substrate for the acetyltransferase ATAT1. We posit that neuronal mishandling of ATAT1 is a common pathogenic feature of axonal forms of Charcot-Marie-Tooth disease, and that regulating ATAT1 activity or localization in sensory neurons offers a therapeutic strategy to inhibit distal axon degeneration while restoring in vivo sensory function.

3) Microtubule-dependent regulation of synaptic function. Decoding the synaptic life of microtubules in health and disease. Given the importance of synaptic dynamic microtubules in neurotransmission and plasticity, we wish to investigate the significance of synaptic microtubules in several neuronal cell types and whether dysregulation of synaptic microtubules can be associated with neurological disease caused by mutations in microtubule regulatory proteins residing at the synapse, such as tau in Alzheimer's disease and tauopathies, a-synuclein in Parkinson's disease, spastin in hereditary spastic paraplegias, and MAP1B and FMRP in fragile X syndrome.