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.
, Bhamidipati A., Thomas S., Schwahn U., Lewis S.A., Cowan N.J.- “Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone Cofactor C” - J Biol Chem
, 2002, 277(17): 14629-14634
Martin-Benito J., Boskovic J., Gomez-Puertas P., Carrascosa J.L., Simons C., Lewis S.A., Bartolini F.
, Cowan N.J. and Valpuesta J.M. – “Structure of eukariotic Prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT” - EMBO J
, 2002, 21(23): 6377-6386
Grayson C, Bartolini F.
, Chapple J.P., Willison K.R., Bhamidipati A., Lewis S.A., Luthert P.J., Hardcastle A.J., Cowan N.J. and Cheetham M.E. - “Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3” - Hum Mol Genet
, 2002, 11(24): 3065-3074
Shern J.F., Sharer J.D., Pallas D., Bartolini F.
, Cowan N.J., Reed M.S., Pohl J and Kahn R. – “ Cytosolic Arl2 is complexed with cofactor D and PP2A” - J Biol Chem
, 2003, 278 (42): 40829-40836
Bloom J., Amador V., Bartolini F.
, De Martino G., and Pagano M. – “Triggering proteosome-mediated degradation of p21 via the ubiquitin system” – Cell
, 2003, 115(1): 71-82 Bartolini F.
,Tian G., Piehl M., Cassimeris L., Lewis S. and Cowan N.J. – “Identification of a novel-tubulin destabilizing protein related to tubulin-chaperone cofactor E” – J Cell Sci, 2005, 118: 1197-1207, (Research Focus in Trends in Cell Biol
, 2005, 15(11): 571-573)Bartolini F.
and Gundersen G.G. “Organization of non-centrosomal microtubule arrays”, J Cell Sci
, 2006, 119(20): 4155-4163
Moseley J. B., Bartolini F.
., Okada K., Wen Y, Gundersen G.G., and Goode B.L. “Regulated binding of Adenomatous polyposis coli (APC) protein to actin”- J Biol Chem
, 2007, 282(17): 12661-12668 Bartolini F.
, Moseley J.B., Schmoranzer J., Goode B.L., and Gundersen G.G. “The formin mDia stabilizes microtubules independently of its actin nucleation activity”- J Cell Biol, 2008, 181(3): 523-536, (Dispatch in Curr Biol
, 2008, 18(14): 605-608)Bartolini F.
and Gundersen G.G. “Formins and microtubules”, Bioch Bioph Acta - Molecular Cell Research for Special Issue: Formins
, 2010, 1803(2): 164-173
Okada K., Bartolini F.
, Deaconescu A., Moseley J. B., Dogic Z., Grigorieff N., Gundersen G.G., and Goode B. L. “The tumor suppressor APC is a potent nucleator of actin assembly that synergizes with formins”- J Cell Biol
, 2010, 89(7): 1087-1096, (In focus in J Cell Biol, 2010, 89(7): 1055)Bartolini F.
, Ramalingam N., and Gundersen G.G. “The formin mDia1 is released from actin filaments to stabilize microtubules ”- MBoC
, 2012, 23(20):4032-40
Andres-Delgado L., et al., Olga M. Anton, Bartolini F.
, Gundersen G.G., and Alonso A.M. “The formin INF2 mediates the formation of arrays of detyrosinated microtubules necessary for reorientation of the centrosome to the immunological synapse of T lymphocytes”- J Cell Biol
, 2012, 198(6):1025-37
Pianu B., Lefort R., Toubier E., and Bartolini F
. “Amyloid-beta1-42 peptide regulates microtubule stability independently of tau”- J Cell Sci
, 2014 Jan 14.
Morris E., Nader G., Ramalingam N., Bartolini F.
, and Gundersen G.G. “Kif4 interacts with EB1 and stabilizes microtubules downstream of Rho-mDia in migrating fibroblasts”- Plos One
, 2014, 9(3): e91568. Bartolini F.
, Andrés-Delgado L., Nik S., Ramalingam N., Alonso M.A., and Gundersen G.G. “An mDia1/INF2 activation cascade facilitated by IQGAP1 regulates stable microtubules in migrating cells”- MBoC
, 2016 March 30.
Taveras, C, Kim C, Bartolini F
, Gundersen G.G. and Mao Y. “Aurora B phosphorylation switches on the actin nucleation activity of the formin mDia3”- (under submission)
Qu X., F.N. Yuan, C. Corona, S. Pasini, X. Wang, R. Lefort, Gundersen G.G., M. Shelanski, and F. Bartolini
. “Formin-mediated Microtubule Hyperstabilization in Amyloid-beta Synaptotoxicity “ (under submission)
Honors and Awards
- “Telethon” Foundation for Muscular Dystrophy and Genetic Disorders Postdoctoral Fellowship2007
- Italian Academy Postdoctoral Fellow2012
- Alzheimer’s Association Young Investigator Award2013
- Schaefer Research Scholar Award 2013
- Alzheimer's Association New Investigator Research Grant2015
- BrightFocus Foundation Standard Award 2015
- Thomson Innovation Award