Biology Department Emeritus Faculty

Our current research interests are focused on the structure and dynamic membrane interactions in abnormal nerve myelin, in which alterations have resulted from experimental, pathological, or genetic conditions. To link structure and composition at the molecular, macromolecular and tissue levels in the nervous system, our studies in these areas have utilized x-ray diffraction, microscopy at the light and ultrastructural levels, a variety of protein and lipid biochemical techniques, and molecular modeling.

What holds myelin together, and how are its constituents targeted in diseases? To characterize the molecular organization of lipids and proteins in nerve myelin membranes, and to define the molecular interactions of its membrane arrays, we have correlated biophysical and biochemical results from different types of specimens (e.g., whole unfixed or fixed tissue from a phylogenetic range of vertebrates, tissue homogenates, tissue fractions and model lipid/protein systems). Among the questions we addressed were: how does the organization of proteins and lipids in myelin account for the inter-membrane interactions of the membranes? What is the structural basis of demyelination? Our findings are relevant to understanding the process of membrane disruption and delamination which occurs in demyelinating diseases such as multiple sclerosis and certain peripheral neuropathies. Our findings have also helped to explain how specific mutations in myelin adhesion proteins or in lipid biosynthetic pathways affect the stability and functionality of the myelin.

• Visigalli D, Capodivento G, Basit A, Fernández R, Hamid Z, Pencová B, Gemelli C, Marubbi D, Pastorino C, Luoma AM, Riekel C, Kirschner DA, Schenone A, Fernández  JA, Armirotti A, Nobbio L (2020) Exploiting spingo- and glycerophospholipid impairment to select effective drugs and biomarkers for CMT1A. Frontiers in Neurology: Neuromuscular Diseases. 11:903. doi: 10.3389/fneur.2020.00903
• Baumann A, Denninger AR, Domin M, Demé B, Kirschner DA (2022) Metabolically-incorporated deuterium in myelin localized by neutron diffraction and identified by mass spectrometry. BioRxiv doi: 10.1101/2021.12.17.473245v3. Current Research in Structural Biology 4:231-245. doi: 10.1016/ j.crstbi.2022.06.00
• Snow AD, Castillo GM, Nguyen BP, Choi PY, Cummings JA, Cam J, Hu Q, Lake T, Pan W, Kastin AJ, Kirschner DA, Wood SG, Rockenstein E, Masliah E, Lorimer S, Tanzi RE, Larsen L (2019) The Amazon rain forest plant Uncaria tomentosa (cat's claw) and its specific proanthocyanidin constituents are potent inhibitors and reducers of both brain plaques and tangles. Scientific Reports, Feb 6;9(1):561. doi: 10.1038/s41598-019-38645-0.
• Colombo L, Stoilova T, Deme B, Inouye H, Booth R, Del Favero E, Rondelli V, Kirschner DA, Cantu L, and Salmona M (2017) The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study. Scientific Reports, Jul 14;7(1):5510. doi: 10.1038/s41598-017-05582-9
• Inouye H, Kuo F-H, Denninger, AR, Weinhause B, Burghammer M, Kirschner DA (2017) Myelin structure in unfixed, single nerve fibers: Scanning x-ray microdiffraction with a beam size of 200 nm. J Structural Biology, Dec;200(3):229-243. doi: 10.1016/j.jsb.2017.07.001
• Ahmed SS, Schattgen S, Frakes AE, Sikoglu EM, Su Q, Li J, Hampton TG, Denninger A, Kirschner DA, Kaspar B, Matalon R, Gao G (2016) rAAV gene therapy in a Canavan's disease mouse model reveals immune impairments and an extended pathology beyond the central nervous system. Molecular Therapy 24(6):1030-41. doi: 10.1038/mt.2016.68. Epub 2016 Apr 4.
• Inouye H, Kirschner DA (2016) Evolution of myelin ultrastructure and the major structural myelin proteins. Brain Research, Oct 28. pii: S0006-8993(15)00808-2. doi: 10.1016/j.brainres.2015.10.037. 
• Denninger AR, Breglio A, Maheras KJ, LeDuc G, Cristiglio V, Demé B, Gow A, Kirschner DA. (2015) Claudin-11 tight junctions in myelin are a barrier to diffusion and lack strong adhesive properties. Biophys J. Oct 6;109(7):1387-1397. doi: 10.1016/j.bpj.2015.08.012. PubMed PMID: 26445439.
• Luoma AM, Kuo F, Cakici O, Crowther MN, Denninger AR, Avila RL, Brites P, Kirschner DA (2015) Plasmalogen phospholipids protect internodal myelin from oxidative damage. Free Radicals in Biology & Medicine, 84:296-310. doi: 10.1016/j.freeradbiomed.2015.03.012.
• Heinecke KA, Luoma AM, d’Azzo A, Kirschner DA, Seyfried TN (2015) Myelin abnormalities in the optic and sciatic nerves in mice with GM1-gangliosidosis. ASN Neuro, Jan-Feb 2015 7: 1759091415568913, first published on February 18, 2015; doi:10.1177/1759091415568913.
• Denninger AR, Demé, B, Cristiglio V, LeDuc G, Feller WB, Kirschner DA (2014) Neutron scattering from myelin revisited: bilayer asymmetry and water-exchange kinetics. Acta Crystallographica D70: 3198-3211. doi: 10.1107/S1399004714023815.
• Inouye H, Liu J, Makowski L, Palmisano M, Burghammer M, Riekel C, Kirschner DA (2014) Myelin organization in the nodal, paranodal, and juxtaparanodal regions revealed by scanning x-ray microdiffraction. PLoS ONE 9(7):e100592. doi: 10.1371/journal.pone.0100592.  http://hdl.handle.net/2345/bc-ir:103602
• Krishnan R, Tsubery H, Proschitsky MY, Asp E, Lulu M, Gilead S, Gartner M, Waltho JP, Davis PJ, Hounslow AM, Kirschner DA, Inouye H, Myszka DG, Wright J, Solomon B, Fisher RA (2014) A bacteriophage capsid protein is a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies. Journal of Molecular Biology 426(13):2500-19. doi: 10.1016/j.jmb.2014.04.015. Epub 2014 Apr 22..
• Da Silva TF, Eira J, Lopes A, Malheiro AR, Sousa V, Luoma AM, Avila RL, Wanders R, Just W, Kirschner DA, Sousa MM, Brites P (2014) Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination, J Clinical Investigation 124(6):2560-70. doi: 10.1172/JCI72063. Epub 2014 Apr 24.
• Ahmed SS, Li H, Cao C, Sikoglu EM, Denninger AR, Su Q, Eaton S, Liso A, Xie J, Szucs S, Zhang H, Moore C, Kirschner DA, Seyfried TN, Flotte TR, Matalon R, and Gao G  (2013) A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene-therapy in Canavan mice. Molecular Therapy 21(12):2136-47. doi: 10.1038/mt.2013.138. Epub 2013 Jul 2.
• Patzkó A, Bai Y, Saporta MA, Katona I, Wu XY, Wrabetz L, Feltri ML, Wang S, Dillon LM, Kamholz J, Kirschner DA, Sarkar F, Shy ME (2012) Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain 135:3551-66.  doi: 10.1093/brain/aws299.
• Saporta MAC, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner DA, Crowther M, Southwood C, Gow A, Wu X, Feltri ML, Wrabetz L, Shy ME (2012) MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth 1B. Brain 135:2032-2047.  doi: 10.1093/brain/aws140.
• Jiang H, Kiebish MA, Kirschner DA, Han X (2012) Multi-dimensional mass spectrometry-based shotgun lipidomics and its application for analysis of PEX7 mouse brain lipidome. In Lipidomics – Technologies and Applications (K Ekroos, ed.), Wiley-VCH, Weinheim, Germany.
• Gilardini A, Avila RA, Luckett R, Lu J, Oggioni N, Rodruguez-Menendez V. Bossi M, Canta A, Cavaletti G, Kirschner DA (2012) Myelin structure is unaltered in chemotherapy-induced peripheral neuropathy. NeuroToxicology 33:1-7.  doi: 10.1016/j.neuro.2011.10.010.
• Echeverria V, Zeitlin R, Burgess S, Patel S, Barman A, Thakur G, Mamcarz M, Wang L, Sattelle DB, Kirschner DA, Mori T, Leblanc R, Prabhakar R, and Arendash GW (2011) Cotinine reduces amyloid-b aggregation and improves memory in Alzheimer’s mice. J Alz Dis 23:1-19. (link to PubMed abstract).
• Avila RA, Inouye H, Feltri ML, Wrabetz L, Kirschner DA (2010) P0 (protein zero) mutation Ser34Cys underlies instability of internodal myelin in S63C mice. J Biol Chem, Oct 11. 285(53):42001-12.
• Inouye, H., Gleason, K.A., Decatur, S.M., Kirschner, D.A. 2010. Differential effects of Phe19 and Phe20 on fibril formation by amyloidogenic peptide Aβ16-22 (Ac-KLVFFAE-NH₂). Proteins: Structure, Function, and Bioinformatics 78: 2306–2321.
• Kirschner, D.A., Avila, R.L., Luoma, A., Enzmann, G.U., Agrawal, D., Inouye, H., Bunge, M.B., Kocsis, J.D., Peters, A., Whittemore, S. 2010. Rapid assessment of internodal myelin integrity in CNS tissue. Journal of Neuroscience Research 88: 712–723.

• Verheijen, M.H., Camargo, N., Nadra, K., de Preux, A.-S., Verdier, V., Luoma, A.M., Crowther, M., Inouye, H., Shimano, H., Chen, S., Brouwers, J., Helms, B.J., Feltri, M.L., Wrabetz, L., Kirschner, D.A., Chrast, R., Smit, A.B. 2009. SREBP cleavage activation protein (SCAP) is required for dynamic synthesis of a proper Schwann cell myelin membrane. Proceedings of the National Academy of Sciences of the United States of America 106: 21383–8.
• Agrawal, D., Hawk, R., Avila, R.L., Inouye, H., Kirschner, D.A. 2009. Internodal myelination during development quantitated using x-ray diffraction. Journal of Structural Biology 168: 521–526.
• Kirschner, D.A., Karthigesan, J., Bizzozero, O.A., Kosaras, B., Inouye, H. 2009. Myelin structure and composition of myelinated tissue in the African lungfish. Neuron Glia Biology 4: 59–70.
• Inouye, H., and Kirschner, D.A. 2008. Myelin: A one-dimensional biological “crystal” for x-ray and neutron scattering. In: Molecules: Aggregation, Nucleation, Crystallization — Beyond Medical and Other Implications (Eds. J. Sedzik, P. Riccio), World Scientific Publishing, Singapore.
• Flores, A.I., Narayanan, S.P., Morse, E., Shick, H.B., Avila, R.L., Kirschner, D.A., and Macklin, W.B. 2008. Constitutively active Akt induces myelination in the central nervous system. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28: 7174–83.
• Kirschner, D.A., Gross, A.A., Hidalgo, M., Inouye, H., Gleason, K., Abdelsayed, G., Castillo, G.M., Snow, A.D., Pozo-Ramajo, A., Petty, S.A., and Decatur, S.M. 2008. Fiber diffraction as a screen for amyloid inhibitors. Current Alzheimer Research 5: 288–307.
• Luo, X.Y., Cerullo, J., Dawli, T., Priest, C., Haddadin, Z., Kim, A., Inouye, H., Suffoletto, B.P., Avila, R.L., Lees, J.P., Sharma, D., Xie, B., Costello, C.E., and Kirschner, D.A. 2008. Peripheral myelin of Xenopus laevis: role of electrostatic and hydrophobic interactions in membrane compaction. Journal of Structural Biology 162: 170–183.
• Luo, X., Inouye, H., Sharma, D., Lee, D., Avila, R.L., Salmona, M., and Kirschner, D.A. 2007. Cytoplasmic domain of zebrafish myelin P0: adhesive role depends on beta-conformation. Biophysical Journal 93: 3515–3528.
• Luo, X.Y., Sharma, D., Inouye, H., Lee, D., Avila, R.L., Salmona, M., and Kirschner, D.A. 2007. Myelin structure and composition in zebrafish. Neurochemical Research 32: 197–209.
• Yin, X., Baek, R.C., Kirschner, D.A., Peterson, A., Fujii, Y., Nave, K.A., Macklin, W.B., and Trapp, B.D. 2006. Evolution of a neuroprotective function of central nervous system myelin. Journal of Cell Biology 172: 469–478.
• Wrabetz, L., D’Antonio, M., Pennuto, M., Dati, G., Tinelli, E., Fratta, P., Previtali, S., Imperiale, D., Zielasek, J., Toyka, K., Avila, R.A., Kirschner, D.A., Messing, A., Feltri, M.L., and Quattrini, A. 2006. Different intracellular pathomechanisms produce diverse MPZ-neuropathies in transgenic mice. Journal of Neuroscience 26: 2358–2368.
• Inouye, H., Sharma, D., Goux, W.J., and Kirschner, D.A. 2006. Structure of core domain of fibril-forming PHF/tau fragments. Biophysical Journal 90: 1774–1789.
• Shinchuk, L. M., Sharma, D., Blondelle, S.Y., Reixach, N., Inouye, H., and Kirschner, D.A. 2005. Poly(L-alanine) expansions form core beta-sheets that nucleate amyloid assembly. Proteins: Structure, Function, and Bioinformatics 61: 579–589.
• Sharma, D., Shinchuk, L.M., Inouye, H., Wetzel, R., and Kirschner, D.A. 2005. PolyGlutamine homopolymers having 8-45 residues form slab-like beta-crystallite assemblies. Proteins: Structure, Function, and Bioinformatics 61: 398–411.
• Avila, R.A., Inouye, H., Baek, R., Yin, X., Trapp, B.D., Feltri, M.L., Wrabetz, L., and Kirschner, D.A. 2005. Structure and stability of internodal myelin in mouse models of hereditary neuropathy. Journal of Neuropathology & Experimental Neurology 64: 976–990.
• Kirschner, D.A., Wrabetz, L., and Feltri, M.L. 2004. The P0 Gene. In: Myelin Biology and Disorders 1, (Ed. R.A. Lazzarini et al.), Elsevier/Academic Press, NY, pp. 523–545.
• Inouye, H., Bond, J.E., Deverin, S.P., Lim, A., Costello, C.E., and Kirschner, D.A. 2002. Molecular organization of amyloid protofilament-like assembly of betabellin 15D: Helical array of beta-sandwiches. Biophysical Journal 83: 1716–1727.
• Thompson, A.J., Cronin, M.S., and Kirschner, D.A. 2002. Myelin protein zero (P0) exists as dimers and tetramers in native membranes of Xenopus laevis peripheral nerve. Journal of Neuroscience Research 67(6): 766–771.

2015        

• “CIDP and Myelin Structural Biology”, Invited lectures (12) as Visiting Professor in Department of Neurological, Neuropsychological, Morphological & Movement Sciences, University of Verona Medical School, Verona, Italy
• "From Macro to Nano: Focusing on Nerve Myelin—Nature's Multilayer Membrane Assembly", Invited colloquium, Physics Department, Boston College (10/14)

2014    

• “Myelin Structural Biology: Probing the Boundaries of Wrap”, Invited talk, Boston Physics of Living Systems Hangout, MIT (4/10)

2013

• “@ & Between the Nodes: What X-rays & Neutrons Reveal About Nerve Myelin”, Invited talk, IBMC, Porto, Portugal (5/9)

2012

• “Nerve Myelin Between the Nodes: What X-rays & Neutrons Reveal“, invited speaker, A.I. DuPont Hospital for Children, Nemours Translational Science Research Seminar Series, Wilmington, Delaware (10/25)
• “Neutron Diffraction from Myelin: Redux >Forty Years”, invited speaker, Symposium: “Structural Dynamics and Dynamical Structures: Future and Challenges of Neutron Scattering in Biology”, Institute Laue-Langevin, Grenoble, France (10/3-10/5).
• “Novel Molecular Views of Nerve Myelin Using Microbeam X-ray Diffraction and Neutron Diffraction”, invited talk, American Crystallographic Association, annual meeting, Boston (7/30).
• “Myelin Structural Biology: Molecular Organization and Dynamic Interactions”, Symposium on Membrane Biology, invited lecture, Acibadem University Medical School, Istanbul, Turkey (5/30)

2011

• “A Sabbatical Report:  Advances in Structural Biology: My Adventures in Milano & Grenoble with X-rays & Neutrons, i Gelati & les Croissants, Ciao & Bonjour”, seminar, Biology Dept, BC (11/1)
• “Nerve Myelin:  A New Rap On An Old Wrap – Pushing the Boundaries of Analysis”, invited seminar, Department of Physiology and Biophysics, Boston University (10/18)
• “New Raps on A Phylogenetically Old Wrap:  From Molecules to Myelinopathies”, invited lecture at the BioCenter Oulu Doctoral Programme Advanced Course in Structural Biology, University of Oulu, Oulu, Finland (5/31)
• “En(w)raptures of Myelin”, invited lecture in “Protein Structure & Disease”, Brandeis University (3/28)

2010

• “Assessing Myelin Development and Structure in Animal Models of Human Disorders “ Istituto di Richerche Farmacologiche Mario Negri”, Milano, Italy (10/11)
• “Structure Determination by X-ray Diffraction”, invited lecture in Biological Chemistry (Bi435), Boston College (4/30)