ProfessorOffice: MRB 235Phone: 970-491-6096Education: Ph.D., University of WisconsinEmail: James.Bamburg@ColoState.eduResearch Title: The cytoskeleton and neurodegenerative disease
Actin filaments (F-actin) constitute a dynamic component of the cytoskeleton of eukaryotic cells. Processes of cellular motility and cell division are dependent upon a pool of actin subunits capable of rapid assembly and disassembly in response to extracellular signals. The interaction of actin with the cell membrane and the spatial and temporal changes in actin organization which underlie cell movement and neuronal pathfinding are largely regulated by a number of actin binding proteins, among the most important of which is actin depolymerizing factor (ADF) and its related family member, cofilin.
ADF and cofilin are 18.5kDa proteins first isolated from vertebrate brain. All eukaryotic organisms including plants and protists have an ADF/cofilin protein. Genetic studies have shown that ADF/cofilins are essential for survival. This family of proteins is required for cell polarization and polarized cell migration such as occurs during development of multicellular organisms and during metastasis of cancer cells. In the nervous system, ADF/cofilins are essential for the initial formation of neurites, for their conversion into axons and dendrites, and for wiring the nervous system through pathfinding of neuronal growth cones. Memory and learning depend on proper regulation of ADF/cofilin in dendritic spines for both insertion of new receptors and for spine remodeling. Both in vitro and in vivo, at low concentration with respect to actin, ADF/cofilin serve to rapidly increase the dynamics of actin filaments but at high concentration they can bind to F-actin and stabilize filaments. Blocking ADF/cofilin activity completely inhibits cellular processes dependent upon actin reorganization. ADF/cofilins also compete for the binding of tropomyosins and myosins on F-actin and thus influence cell contractile process though mechanisms other than actin depolymerization.
ADF/cofilins in multicellular organisms are regulated by phosphorylation of a single serine residue near the N-terminus of the protein. Since transmembrane signaling culminates in changes in the activity of protein kinases or phosphatases, ADF/cofilins are key proteins through which extracellular ligands bring about an alteration in cytoskeletal organization. In neuronal growth cones, this actin reorganization is the key to pathfinding by many extracellular guidance cues.
ADF/cofilins play a major role in neurodegenerative diseases. They are rapidly activated (dephosphorylated) in response to energy depletion or oxidative stress. In many cells including neurons, this hyperactivation results in the formation of cytoplasmic rods containing actin saturated (1:1 complex) with ADF/cofilin. Rods are abundant in human brain from mild cognitively impaired subjects, an early stage of dementia, and in Alzheimer brain. Rods are induced experimentally in primary neuronal cultures by excitotoxic glutamate, amyloid-β peptides, and proinflammatory cytokines such as TNFα. Rods contain oxidized cofilin dimers, suggesting that oxidative stress accompanies rod-inducing signals. The signaling pathway for rod formation from amyloid-β peptides and TNFα requires the cellular prion protein, which indirectly causes activation of NADP oxidase to generate reactive oxygen species.
Current research in my laboratory is addressing the role of ADF/cofilin in neurodegenerative diseases. We make and use viral vectors for expressing proteins in neuronal cultures and use computer imaging of confocal fluorescence images to quantify rods and analyze cell behavior.
Flynn KC, Hellal F, Neukirchen D, Jacobs S, Tahirovic S, Dupraz S, Stern S, Garvalov BK, Gurniak C, Shaw A, Meyn L, Wedlich-Soldner R, Bamburg JR, Small JV, Witke W, Bradke F. (2012) Neuron 76, 1091-1107. PMID: 23259946
Wiggan O, Shaw AE, DeLuca JG, Bamburg JR. (2012) Dev Cell 22, 530-543. PMID: 22421043
Mendoza-Naranjo A, Otth C, Henriquez DR, Bamburg JR, Maccioni RB, Gonzalez-Billault C. (2012) J Alz Dis. 29, 63-77. PMID: 22204905
Bernstein BW, Shaw AE, Minamide LS, Pak CW, Bamburg JR. (2012) J Neurosci 32, 6670-6681. PMID: 22573689
Maloney MT, Bamburg JR. (2011) Mechanisms of neuronal growth cone guidance: An historical perspective. Dev Neurobiol 71, 795-800 PMID:21805682
Bamburg JR (2011) Non-phagocytic host cell invasion: a new role for cofilin in coordinating actin dynamics and membrane lipids. Mol Microbiol 81, 851-854. PMID: 21762221
Whiteman IT, Minamide LS, Goh DL, Bamburg JR, Goldsbury C. (2011) Rapid changes in phospho-MAP/tau epitopes during neuronal stress: cofilin-actin rods primarily recruit microtubule binding domain epitopes. PLoS ONE 6, e20878 PMID: 21738590
Munsie L, Caron N, Atwal RS, Marsden IT, Wild EJ, Bamburg JR, Tabrizi SJ, Truant R. (2011) Mutant huntingtin causes defective actin remodulation during stress: defining a new role of transglutaminase 2 in neurodegenerative disease. Hum Mol Genetics 20, 1937-1951. PMID:21355047
Davis RC, Marsden IT, Maloney MT, Minamide LS, Podlisny M, Selkoe DJ, Bamburg JR. (2011) Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin phosphorylation. Mol Neurodegen 6, 10. PMID: 21261978
Marsden IT, Minamide LS, Bamburg JR. (2011) Amyloid-ß-induced amyloid-ß secretion: A possible feed-forward mechanism in Alzheimer disease. J. Alzheimers Dis 24, 681-692. PMID:21297255
Creed SJ, Desouza M, Bamburg JR, Gunning P, Stehn J. (2011) Tropomyosin isoform 3 promotes the formation of filopodial by regulating the recruitment of actin binding proteins to actin filaments. Exp Cell Res. 317, 249-261 PMID:21036167
Bernstein BW, Maloney MT, Bamburg JR. (2011) Actin and diseases of the nervous system. In Neurobiology of Actin G. Gallo and LL Lanier, Eds., Springer, NY. Pp. 201-234.
Chiu TT, Patel N, Shaw AE, Bamburg JR, Klip A. (2010) Arp2/3 and cofilin-coordinated actin dynamics are required for insulin-mediated GLUT4 translocation to the surface of muscle cells. Mol Biol Cell 21, 3529-3539 PMID:20739464
Gu J,Lee CW, Fan Y, Komols D, Tang X, Sun C, Chen G, Yu K, Hartzell HC, Bamburg JR, Zheng JQ. (2010) ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci 13, 1208-1215 (2010) PMID: 20835250
Bamburg JR, Bernstein BW. (2010) Roles of ADF/cofilin in actin polymerization and beyond. F1000 Biol Rep 2, 62. PMID:21173851
Karlsson AB, Maizels ET, Flynn MP, Jones JC, Shelden EA, Bamburg JR, Hunzicker-Dunn M. (2010) Luteinizing hormone receptor-stimulated progesterone production by preovulatory granulosa cells requires protein kinase A- dependent activation/dephosphorylation of the actin dynamizing protein cofilin. Mol Endocrinol 24, 1765-1781. PMID: 20610540
Marsick BM, Flynn KC, Santiago-Medina M, Bamburg JR, Letourneau PC. (2010) Activation of ADF/cofilin mediates attractive growth cone turning toward nerve growth factor and netrin-1. Dev Neurobiol 70, 565-588. PMID: 20506164
Bamburg JR, Bernstein BW, Davis RC, Flynn KC, Goldsbury C, Jensen JR, Maloney MT, Marsden IT, Minamide LS, Pak CW, Shaw AE, Whiteman IT, Wiggan O. (2010). ADF/cofilin-actin rods in neurodegenerative diseases. Curr Alzheimer Res 7, 241-250. PMID: 20088812
Minamide LS, Maiti S, Boyle JA, Davis RC, Coppinger JA, Bao Y, Huang TY, Yates J, Bokoch GM, Bamburg JR. (2010) Isolation and characterization of cofilin-actin rods from stressed cells. J Biol Chem 285, 5450-5460.PMID: 20022956
Pak CW, Bamburg JR. (2009) Exciting dendritic spines. The Open Neurosci J 3, 52-53.
Whiteman IT, Gervasio OL, Cullen KM, Guillemin GJ, Jeong EV, Witting PK, Antao ST, Minamide LS, Bamburg JR, Goldsbury C. (2009) Activated ADF/cofilin sequesters phosphorylated microtubule associated protein during assembly of Alzheimer-like neuronal cytoskeletal striations J Neurosci 29, 12994-13005. PMID: 19828813
Flynn KC, Pak CW, Shaw AE, Bradke F, Bamburg JR. (2009). Growth cone-like waves transport actin and promote axonogenesis and neurite branching. Dev. Neurobiol. 69, 761-779. PMID:19513994
Bamburg JR, Bloom GS. (2009). Cytoskeletal pathologies of Alzheimer disease. Cell Motil Cytoskel. 66, 635-649. PMID: 19479823
Davis RC, Maloney MT, Minamide LS, Flynn KC, Stonebraker MA, Bamburg JR. (2009) Mapping cofilin-actin rods in stressed hippocampal slices and the role of cdc42 in amyloid ß-induced rods. J. Alzheimers Dis 18, 35-50. PMID:19542631
Lee CW, Han J, Bamburg JR, Han L, Lynn R, Zheng JQ. (2009) Spatial control of acetylcholine receptor clustering on postsynaptic membrane by ADF/cofilin-directed vesicular trafficking. Nature Neurosci. 12, 848-856.PMID: 19483689
Kuhn TB, Bamburg JR. (2008) Tropomyosin and ADF/Cofilin as collaborators and competitors. In: Tropomyosin P.G. Gunning, Ed., Landes Bioscience, NY. Adv. Exp. Med. Biol. 644, 232-249. PMID:19209826
Huang TY, Minamide LS, Bamburg JR, Bokoch GM. (2008) Chronophin serves as an ATP-sensing mechanism for cofilin dephosphorylation and neuronal cofilin-actin rod formation. Dev. Cell 15, 691-703. PMID:19000834
Thoms J, Loch H, Bamburg JR, Gunning P, Weinberger R. (2008) A tropomyosin 1 induced defect in cytokinesis can be rescued by elevated expression of cofilin. Cell Motil. Cytoskel. 65, 979-990. PMID:18937355
Fass J, Pak CW, Bamburg JR, Mogilner A. (2008). Stochastic simulation of actin dynamics reveals the role of annealing and fragmentation. J Theor. Biol. 252, 173-183.PMID:18279896
Pak CW, Flynn KC, Bamburg JR (2008) Actin binding proteins take the reigns in growth cones. Nature Rev Neurosci 9, 136-147. PMID:18209731
Garvalov BK, Flynn KC, Neukirchen D, Meyn L, Teusch N, Wu X, Brakebusch C, Bamburg JR, Bradke F. (2007) Cdc42 regulates cofilin during the establishment of neuronal polarity. J. Neurosci. 27, 13117-13129. PMID:18045906
Mseka T, Bamburg JR, Cramer LP. (2007) ADF/cofilin controls formation of oriented actin filament bundles in the cells body to trigger fibroblast polarization. J Cell Sci. 120, 4332-4344. PMID:18042624
Domazetovska A, Ilkovski B, Cooper ST, Ghoddusi M, Hardeman EC, Minamide LS, Gunning P, Bamburg JR, North KN. (2007) Mechanisms underlying actin aggregate formation inside the nucleus. Brain 130, 3275-3284. PMID:17928315
Wen Z, Han L, Bamburg JR, Shim S, Ming G-l, Zheng JQ. (2007) BMP molecules guide growth cones by a balancing act of LIM kinase and slingshot phosphatase on ADF/cofilin. J. Cell Biol. 178, 107-119. PMID:17606869
Maloney MT, Bamburg JR (2007) Cofilin-mediated neurodegeneration in Alzheimer's disease and other amyloidopathies.Mol. Neurobiol. 35, 21-43. PMID:17519504
Maloney MT, Kinley A, Pak C, Bamburg JR. (2007) ADF/cofilin, actin dynamics and disease. In Actin-Binding Proteins and Disease. C. dos Remedios and D. Chhabra (Eds). Springer, New York. Protein Reviews 8, 83-187.