Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER

 

Columbia University
Medical Center
Neurological Institute

710 West 168th Street, 3rd floor
(212) 305-1818


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About Us

Taub Faculty


Francesca Bartolini, PhD

Francesca Bartolini, PhD

Assistant Professor of Pathology and Cell Biology

Email: fb2131@columbia.edu
Tel: 212-305-3708

Research Summary:

Neurons possess extensive tubulin post-translational modifications 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 post-translational modifications are implicated in the regulation of MAPs, MT severing enzymes and binding to motors. Synaptic activation also appears to locally regulate post-translational modifications associated with MT stability. Thus, localized increases in MT stability in neurons have the potential to 1) impair MT-dependent axonal and dendritic trafficking; 2) disrupt synaptic transmission leading to spine collapse; 3) induce tubulin post-translational modifications that interfere with MT binding affinity of MT severing enzymes and MAPs such as tau protein.

My laboratory studies the role of MT stability and its regulation in neurodegenerative disease. We are primarily investigating roles for formins, a class of actin and MT stability regulators that act downstream of Rho GTPases activation. We found that amyloid beta (Aβ) induces the formation of a subset of stable detyrosinated MTs through RhoA and formin activities. Preliminary characterization of the pathway shows that MT stabilization by Aβ is regulated by integrin signaling and initiated by APP-dimerization and caspase activities, linking the induction of MT stability to Aβ-mediated neurotoxicity.

Based on these observations, our current work examines whether induction of this subset of stable MTs in neurons, in contrast to MT destabilization that occurs at a later stage, is a primary cause of the loss of synaptic activity and neurotoxicity caused by Aβ. If so, synaptic dysfunction/loss, which is believed to be the primary degenerative effect of Aβ, could result from at least three mechanisms: 1) stabilization of the dynamics of individual MTs in dendritic spines, eventually leading to their collapse; 2) indirect stimulation of tau phosphorylation and missorting into a dendritic compartment as a stress response to increased stable detyrosinated MTs; 3) recruitment of severing enzymes such as spastin or katanin that act on stable MTs.

Given the close association of synapse dysfunction/loss with the onset of various neuropathological disorders such as Alzheimer's and Parkinson's disease, we are also testing whether induction of MT stability is a general property of other amyloids and an early cause of dysfunctional organelle trafficking and degradation, key cellular functions that go awry in progressive neurodegenerative disorders.

To tackle these questions, we employ biochemical and cell-biological approaches using immortalized non-neuronal cells, primary neuronal cultures and animal models of disease. Our work aims to shed light on the molecular nature of the link between amyloids and cytoskeletal changes and provide novel targets for therapeutic strategies to rescue impairment of cell function and cognition in neurodegenerative disease.

Education and Training:

PhD: New York University New York, 2004




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