James Bamburg

James BamburgProfessor
Office: MRB 235
Phone: 970-491-6096
Education: Ph.D., University of Wisconsin
Email: James.Bamburg@ColoState.edu
Research 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 that underlie cell movement are largely regulated by a number of actin binding proteins, among the most important being cofilin and its related family member, actin depolymerizing factor (ADF).

ADF and cofilin are 18.5kDa proteins first isolated from vertebrate brain. All eukaryotic organisms, including plants and protists, express an ADF/cofilin-related protein. Genetic studies have shown that ADF/cofilins are essential for normal cell division and thus organismal maturation and survival, as well as for cell polarization and polarized cell migration such as occurs during development of multicellular organisms or 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 regulate myosin II binding to F-actin and thus influence cell contractile process though mechanisms other than actin depolymerization.

In multicellular organisms, ADF/cofilins 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. This is demonstrated in the adjacent figure in which a hot scale is used to show the immunostaining ratio of total cofilin/phospho-ADF/cofilin.  In the top image where no attractive or repulsive cues are provided, a growth cone has active cofilin (brighter colors) along the entire leading edge. In the lower image a growth cone is being repulsed by a stripe of aggrecan and shows the most active cofilin toward the edge moving away from the repulsive cue.

ADF/cofilins also play key roles in neurodegenerative diseases.  They are rapidly activated (dephosphorylated) in response to energy depletion or oxidative stress. In many cell types, this hyperactivation results in the formation of cytoplasmic rods containing filaments of actin in a 1:1 complex with ADF/cofilin.  Figure shows cofilin-immunostained rods in 6 day in vitro neuronal cultures transiently depleted of ATP for 30 min. Scale bar is 10 µm.

In neurons, rods form within dendrites and axons where they impair delivery of essential cargoes. Rods are often abundant in human hippocampus from subjects suffering from dementia, such as in Alzheimer disease. 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 expression of cellular prion protein, which is in the pathway leading to production of reactive oxygen species by membrane NADP oxidase.  Sequestering of cofilin into rods may also affect the structure and dynamics of dendritic spines

Schematic of dendritic spine showing some of the pathways regulating cofilin activity and actin dynamics during the processes of long-term potentiation (LTP) and long-term depression (LTD). In mouse models of various neurodegenerative diseases or behavioral disorders, treatment with cell penetrating peptides that presumably modulate cofilin phosphoregulation, reverse the deficits of the disease/disorder.

Current research in my laboratory is addressing the role of ADF/cofilin in neurodegenerative diseases and brain disorders, including stroke. We have developed a new method of brain slice culture that allows us to follow the identical neurons over many weeks using fluorescence microscopy. We make and use viral vectors for expressing proteins in a cell-type specific manner and utilize computer imaging of confocal fluorescence images to quantify rods and analyze cell behavior and neuronal circuitry.

We also study the role of cytoplasmic contractility, regulated by competition between ADF/cofilin and myosin II, on the nuclear envelope, the nuclear uptake of mechanosensitive transcription factors, and on the structure of chromatin.  The methylation of different lysine residues of histones within chromatin is indicative of active or repressed chromatin and this pattern changes in response to ADF/cofilin silencing.  In the figure attached, nuclear shape changes are evident in ADF/cofilin silenced cells as is the distribution of histone 3 methylation on two lysines, K27 and K4.

Selected Publications

Shaw AE, Bamburg JR. (2017) Pharmacol Ther. 175, 17-27. PMID:28232023

Wiggan O, Schroder B, Krapf D, Bamburg JR, DeLuca JG. (2017) Sci Rep 7:40953 PMID:28102353

Bamburg JR, Bernstein BW. (2016) Cytoskeleton (Hoboken) 73, 477-497. PMID:26873625

Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL, Mukaetova-Ladinska E, Ihara M, Srivastava S, Padma Srivastava MV, Masters CL, Kalaria RJ, Anand A. (2015)   J. Alzheimer’s Dis 47, 815-843. PMID:26401762

Woo JA, Boggess T, Wang X, Kahn H, Cappos G, Joly-Amado A, De Narvaez E, Majid S, Minamide LS, Bamburg JR, Morgan D, Weeber E, Uhlar C, Kang, D. (2015)  Cell Death Disease 6:1676 PMID:25741591

Subramanian K, Gianni D, Balla C, Assenza GE, Joshi M, Semigran MJ, Macgillivray TE, Van Eyk JE, Agnetti G, Paolocci N, Bamburg JR, Agrawal PB, del Monte F. (2015) J Am Col Cardiol 65, 1199-1214 PMID: 25814227

Walsh KP, Kuhn TB, Bamburg JR. (2014)  Prion 8, 375-380. PMID:25426519

Walsh KP, Minamide LS, Kane SJ, Shaw AE, Brown DR, Pulford B, Zabel MD, Lambeth JD, Kuhn TB, Bamburg JR. (2014)   PLoS One 9, e95995. PMID:24760020

Mi J, Shaw AE, Pak CW, Walsh KP, Minamide LS, Bernstein BW, Kuhn TB, Bamburg JR. (2013) PLoS One 8, e83609 PMID:24391794

Mi J, Shaw AE, Pak CW, Walsh KP, Minamide LS, Bernstein BW, Kuhn TB, Bamburg JR. (2013)  PLoS One 8, e83609 PMID:24391794

Tahtamouni LH, Shaw AE, Hasan MH, Yasin SR, Bamburg JR. (2013)  BMC Cell Biol 14, 45.  PMID: 24093776

Vitriol EA, Wise AL, Berginski ME, Bamburg JR, Zheng JQ. (2013)  Mol Biol Cell 24, 2238-2247.  PMID:23676663

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.

NIH PubMed Publications List