Pharmacology & Physiology
NAME: POSITION TITLE:
Joseph J. McArdle, Ph.D. Professor
INSTITUTION AND LOCATION DEGREE YEAR(S) FIELD OF STUDY
University of Delaware, Newark, DE B.A. 1967 Biology & Chemistry
State University of New York, Buffalo, NY PhD 1972 Cellular Neuropharmacology
My research is conducting four interrelated studies of the neuromuscular junction (NMJ). These research topics and years of experience in the study of the NMJ provide us with unique qualifications for the discovery of treatments for ALS. Dr. Carmen Garcia (University of Venezuela, Caracas) and I are investigating the molecular basis for motor nerve terminal and muscle endplate alterations during diabetes. From February to June in 2010, I worked with Dr. Veit Witzemann at the Department of Molecular Neurobiology of the Max Planck Institute for Medical Research in Heidelberg. The basic goal of my long term collaboration with Dr. Witzemann is to understand the contribution of the embryonic to adult shift of the acetylcholine receptor subtype in development and stability of the NMJ. To achieve this goal, we follow maturation of the NMJ in three lines of mice with genetically altered muscle endplate proteins developed by Dr. Witzemann. The third project deals with the development of antidotes to botulinum neurotoxin A (BoNT/A). This project involves collaborative work with scientists searching for antidotes to BoNT/A. My laboratory has described the action of potential antidotes to BoNT/A developed by Drs. James J. Schmidt (Fort Detrich) and Kim D. Janda (Scripps Research Institute). Our study of BoNT/A is relevant to the proposed study of ALS since we have recently observed that non-paralytic doses of BoNT/A reduce the probability of acetylcholine release from motor nerve endings similar to the defect that we have reported for NMJs of SOD1 G93A mice. The fourth focus of research in my laboratory is to define the role of muscle specific tyrosine kinase (MuSK) in retrograde signaling from muscle to nerve that is essential to motor neuron health. It is not currently understood why Myasthenia Gravis due to MuSK autoantibodies, or mutations of MuSK, is associated with defects of the motor nerves. My study of human umbilical cord blood cells in the therapy of ALS began in collaboration with Dr. Norman Ende (NJ Medical School) in 2003. Since then, we have shown that SOD1 G93A mice treated with human umbilical cord blood cells have improved motor nerve function that may contribute to the prolonged life span these mice experience in response to the treatment protocol that Dr. Ende had previously developed. Our findings are relevant since any therapy for ALS must improve motor nerve function and we have described a model for quantifying such an action. Overall, my laboratory’s years of experience studying the NMJ provides a unique environment for the development of treatments for ALS.
Positions and Honors
1972-1982 Assistant to Associate Professor of Pharmacology, NJ Medical School (UMDNJ)
1979-1980 Visiting Scientist, Lab Cellular Neurobiology, CNRS, Gif-sur-Yvette, France
1979-1980 Fellowship from the Research Foundation of the French Pharmaceutical Industry
1982-Pres Professor of Pharmacology & Physiology, NJ Medical School
1987 (7 Months) Visiting Scientist, Dept Physiol, John Curtin School of Med Research, Canberra, Australia
1987 Fellowship from the Australian National University, Canberra, Australia
1987 (4 Months) Visiting Scientist, Lab Developmental Neurobiology, NICHHD, Bethesda, MD
1991-Present Professor of Anesthesiology, NJ Medical School
1992-Present Adjunct Assoc Prof of Bio-Medical Engineering, NJ Institute of Technology, Newark
1991 Award, Dept Cell & Molec Biol, Commissariat for Atomic Energy, Saclay, France
1990-1991 Member, NSF Cellular Neuroscience Review Panel
1991-1994 Member, NINDS Neurology B1 Study Section
2006, 2007 Member (Ad Hoc) NINDS study section Neurological Sciences and Disorders C
2006 Member (Ad Hoc) NINDS special emphasis, Counter Measures Against Chemical Threats
2010 (6 Months) Visiting Scientist, Max Planck Institute for Medical Research, University of Heidelberg
2011-present Member NIH Spec Emphasis Pan, Fellowships: Biophysical and Physiological Neuroscience
Selected peer-reviewed publications (in chronological order, selected from more than 100; papers dealing with neuromuscular junction and/or relevant to this proposal are in italic font)
1. McArdle, JJ and EX Albuquerque. 1973 . A study of the reinnervation of fast and slow mammalian muscles. J Gen Physiol 61:1‑23. doi:10.1085/jgp.61.1.1
2. McArdle, JJ. 1975. Complex end‑plate potentials at the regenerating neuromuscular junction of the rat. Exp Neurol 49:629‑638. doi:10.1016/0014-4886(75)90048-5
3. McArdle, JJ and FM Sansone. 1977. Reinnervation of fast and slow mammalian muscle following nerve crush at birth. J Physiol (London) 271:567‑586.
4. Sellin, LC and JJ McArdle. 1977. Colchicine blocks neurotrophic regulation of the resting membrane potential in reinnervating skeletal muscle. Exp. Neurol. 55:483‑492. doi:10.1016/0014-4886(77)90016-4
5. McArdle, JJ, L Michelson, and AJ D'Alonzo. 1980. Action potentials in fast‑ and slow‑twitch mammalian muscles during reinnervation and development. J Gen Physiol. 75:655‑672.
6. Bournaud, R, D, Angaut‑Petit, JJ McArdle, and A Mallart. 1980. Abnormal nerve function in hereditary motor end‑plate disease (med) of the mouse. In: Bauman, N., ed. Neurological Mutations Affecting Myelination. INSERM Symposium No. 14 Elsevier/North Holland Biomedical Press.
7. D'Alonzo, AJ and JJ McArdle. 1982. An evaluation of fast‑ and slow‑ twitch muscle from rats treated with 20,25‑diazacholesterol. Exp Neuro. 78:46‑66.
8. McArdle, JJ, D Angaut‑Petit, A Mallart, R Bournaud, L Faille, and JL Brigant. 1981. Advantages of the triangularis sterni muscle of the mouse for investigation of synaptic phenomena. J Neurosci Meth 4:109‑115. doi:10.1016/0165-0270(81)90044-3
9. Angaut‑Petit, D, JJ McArdle, A Mallart, R Bournaud, M Pincon‑Raymond, and F Rieger. 1982. Electrophysiological and morphological studies of a motor nerve in motor end‑plate disease of the mouse. Proc Roy Soc B 215:117‑125.
10. McArdle, JJ 1983. Molecular aspects of the trophic influence of nerve on muscle. Prog Neurobiol 21:135-198. doi:10.1016/0301-0082(83)90001-1
11. Arena, JP, JJ McArdle, and S Laxminarayan. 1986. Characterization of the class I antiarrhythmic activity of cibenzoline succinate in guinea pig papillary muscle. J Pharmacol Exp Therap 240:441‑450.
12. McArdle, JJ, LC Sellin, AJ D'Alonzo, and TM Argentieri. 1987. Reinnervating muscle as a model for the study of neurotrophic mechanisms. In Benzi, G., ed. Advances in Myochemistry:1. John Libbey Eurotext. pp 107‑114.
13. Gage, PW, JJ McArdle, and DA Saint. 1990. Effects of butanedione monoxime on neuromuscular transmission. Br J Pharmacol 100:467‑470.
14. Huang, G‑J and JJ McArdle. 1992. Novel suppression of a neuronal L‑type calcium channel in neurons of murine dorsal root ganglia by the chemical phosphatase 2,3‑butanedione monoxime. J Physiol (London), 447:257‑274.
15. Argentieri, T, SP Aiken, S Laxminarayan, and JJ McArdle. 1992. Physiology of regenerating neuromuscular junctions in the rat, and the effect of 2,3‑butanedione monoxime. Pflügers Archiv European J Physiol 421:256‑261. doi:10.1007/BF00374835
16, Aiken, SP, LC Sellin, JJ Schmidt, SA Weinstein, and JJ McArdle. 1992. Effects of a peptide toxin from Trimeresurus Wagleri on functioning of the rat neuromuscular junction. Pharmacol Toxicol 70:459‑462.
17. Huang, G‑J and JJ McArdle. 1993. Chronic ingestion of ethanol increases the number of Ca2+ channels of hippocampal neurons of long‑sleep but not short‑sleep mice. Brain Research 615:328‑330. doi:10.1016/0006-8993(93)90044-N
18. Sellin, LC and JJ McArdle. 1994. Multiple effects of 2,3-butanedione monoxime (BDM). Pharmacol & Toxicol 74:305-313.
19. Brightman, T, J‑H Ye, E Ortiz‑Jimenez, EJ Flynn, W‑H Wu, and JJ McArdle. 1995. 2,3‑butanedione monoxime protects mice against the convulsant effect of picrotoxin by facilitating GABA‑activated currents. Brain Research 678:110‑116. doi:10.1016/0006-8993(95)00175-P
20. Xiao, Y‑F and JJ McArdle. 1995. Effects of 2,3‑butanedione monoxime on blood pressure, myocardial Ca2+ currents and action potentials of rats. Am J Hypertension 8: 1232‑1240. doi:10.1016/0895-7061(95)00251-0
21. Sellin, LC, K Mattila, A Annila, M Hyvonen, JJ Schmidt, TT Rantala, T Kivisto, and JJ McArdle. 1996. Conformational analysis of a toxic peptide from Trimeresurus Wagleri. Biophys J, 70: 3‑13.
22. Ye, J-H and JJ McArdle. 1996. 2,3-Butanedione monoxime modifies the glycine-gated chloride current of acutely isolated murine hypothalamic neurons. Brain Research 735:20-29. doi:10.1016/0006-8993(96)00546-X
24. Li, X-Y and JJ McArdle. 1997. Novel transient outward K+ current of mature murine hippocampal neurons. Pflügers Archiv European J Physiol 434:195-202. doi:10.1007/S004240050383
25. Ye, J-H and JJ McArdle.1997. Waglerin-1 modulates GABA activated current of murine hypothalamic neurons. J Pharmacol Exp Therap 282:74-80.
26. Routh, VH, JJ McArdle, and BE Levin. 1997. Phosphorylation modulates the activity of the ATP-sensitive K+ channel in the ventromedial hypothalamic nucleus. Brain Research 778:107-119. doi:10.1016/S0006-8993(97)01043-3
27. McArdle, JJ, TL Lentz, V Witzemann, H Schwarz, SA Weinstein, and JJ Schmidt. 1999. Waglerin-1 selectively blocks the epsilon form of the muscle nicotinic acetylcholine receptor. J Pharmacol Exp Therap 289:543-550.
28. Ye, J-H, J Ren, K Krnjevic, PL Liu, and JJ McArdle. 1999. Cocaine and lidocaine have additive inhibitory effects on the GABAA current of acutely dissociated hippocampal neurons. Brain Research 821:26-32. doi:10.1016/S0006-8993(98)01372-9
29. Ye, J-H, L Tao, J Ren, R Schaefer, K Krnjevic, PL Liu, DA Schiller, and JJ McArdle. 2001. Ethanol potentiation of glycine responses in dissociated neurons of rat ventral tegmental area. J Pharmacol Exp Therap 296:77-83. doi:10.1124/jpet.102.033894
30. Ye, J-H, L Tao, L Zhu, K Krnjevic, and JJ McArdle. 2001. Ethanol inhibition of glycine-activated responses in neurons of ventral tegmental area of neonatal rats. J Neurophysiol 86:2426-2434. PMID: 11698532
31. Song, Z, BE Levin, JJ McArdle, N Bakhos, and VH Routh. 2001. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus (VMN). Diabetes 50:2673-2681. doi:10.2337/diabetes.50.12.2673
32. Molles, BE, P Rezai, EF Fine, JJ McArdle, SM Sine, and P Taylor. 2002. Identification of the α and ε subunit interfaces mediating species selectivity of Waglerin-1 for nicotinic acetylcholine receptors. J Biol Chem 277:5433-5440. doi:10.1074/jbc.M109232200
33. Cho, KJ, KA Trzaska, SJ Greco, JJ McArdle, FS Wang, J.-H. Ye, and P. Rameshwar. 2005. Neurons derived from human mesenchymal stem cells show synaptic transmission and cab be induced to produce the neurotransmitter substance P by interleukin-1. Stem Cells 23: 383-391. doi:10.1634/stemcells.2004-0251
34. McArdle, JJ LC Sellin,, KM Coakley, JG Potian, MC Quinones-Lopez, CA Rosenfeld, LG Sultatos, and K Hognason. 2005. Mefloquine inhibits cholinesterases at the mouse neuromuscular junction. Neuropharmacol 49:1132-1139. doi:10.1016/j.neuropharm.2005.09.011
35. Souayah, N, H Karim, S Kamin, J McArdle, and S Marcus. 2006. Severe botulism after focal injection of botulinum toxin. Neurology 67:1855-1856.
36. Yampolsky, P, S Gensler, J McArdle, and V Witzemann 2008. AChR channel conversion and AChR-adjusted neuronal survival during embryonic development. Molecular Cellular Neuroscience 37: 634-645. doi:10.1016/j.mcn.2007.12.014
37. Teichert, RW, CC Garcia, JG Potian, JJ Schmidt, V Witzemann, BM Olivera, and JJ McArdle. 2008 Peptide-toxin tools for probing the expression and function of fetal and adult subtypes of the nicotinic acetylcholine receptor. Annals New York Academy Science 1132: 61–70. doi:10.1016/j.mcn.2007.12.014
38. Liu, Y, D Padgett, M Takahashi, H Li, A Sayeed, RW Teichert, BM Olivera, JJ McArdle, WN Green, and W Lin. 2008. Essential roles of acetylcholine receptor gamma-subunit in neuromuscular junction patterning. Development 135: 1957-1967. doi:10.1242/dev.018119
39. Oppenheim, RW, J Calderó, D Cuitat, J Esquerda, JJ McArdle, BM Olivera, D Prevette, and RW Teichert. 2008. The rescue of developing avian motoneurons from programmed cell death by a selective inhibitor of the fetal muscle-specific nicotinic acetylcholine receptor. Developmental Neurobiology 68: 972-980. doi:10.1002/dneu.20636
40. Souayah, N, JG Potian, CC Garcia, N Krivitskaya, C Boone, VH Routh, JJ McArdle. 2009. Motor Unit Number estimate (MUNE) as a predictor of motor dysfunction in an animal model of type I diabetes: Importance of MUNE in diabetes. Am J Physiol Endocrinol Metab. 297(3): E602-608.
41. Thyagarajan, B, N Krivitskaya, JG Potian, K Hognason, CC Garcia and JJ McArdle. 2009. Capsaicin protects mouse neuromuscular junctions from the neuroparalytic effects of botulinum neurotoxin A. J Pharmacol Exp Therap 331: 361-371.
42. Thyagarajan, B, CC Garcia, JJ Potian, K Hognason, K Čapková, ST Moe, AR Jacobson, KD Janda, and JJ McArdle. Small molecule hydroxamate metalloendoprotease inhibitors antagonize the acute paralytic action of botulinum neurotoxin A. Neuropharmacology (2010), doi:10.1016/j.neuropharm.2010.02.014
43. Ho, MF, M Pires-Alves, L Chang, B Thyagarajan, JE Bloom, Z Gu, KK Aberle, JJ McArdle, and BA Wilson. Recombinant Botulinum Neurotoxin A Heavy Chain-based Delivery Vehicles for Neuronal Cell Targeting. Protein Engineering, Design and Selection, doi: 10.1093/protein/gzq093
44. Pacifici, PG, P Christoph, P Yampolsky, M Koenen, JJ McArdle and V Witzemann. Novel mouse model reveals distinct activity-dependent and –independent contributions to synapse development. 2011. PLOS One 6: 1- 13.
45. Souayah, N, KM Coakley, R Chen, N Ende, and JJ McArdle. Defective neuromuscular transmission in the SOD1G93A transgenic mouse improves after administration of human umbilical cord blood cells. Stem Cell Reviews and Reports, In Press.
46. Potian, JG, B Thyagarajan, K Hognason, F Lebeda, JJ Schmidt, and JJ McArdle. Investigation of “CRATKML” derived peptides against botulinum neurotoxin A poisoning in vivo and in vitro. The Botulinum Journal, In Press.
47. Potian, JG, V Patel, JJ McArdle, B Thyagarajan. 2010.The inveterate botulinum neurotoxin A ushers in exo-endocytic crypts. The Botulinum J., In Press.
48. Garcia CC, JG Potian, C Boone, N Krivitskaya, K Högnason, B Thyagarajan, L. G. Sultatos, VH Routh, and JJ McArdle. Acetylcholinesterase downregulation contributes to neuromuscular junction dysfunction in experimental type I diabetic neuropathy. Submitted.
49. Garcia CC, B Thyagarajan, V Patel, K Högnason, N Krivitskaya, JG Potian, VH Routh, and JJ McArdle. Role of the Agrin-MuSK signaling pathway in postsynaptic fragmentation during STZ induced diabetic neuropathy. Submitted.
50. Chevessier, F, C Peter, U Mersdorf, E Girard, E Krejci, JJ McArdle, V Witzemann. A new mouse model for slow-channel congenital myasthenic syndromes induced by the AChR εL221F mutation. Submitted.
Ongoing Research Support
(CMB) DTRA1-06-CMB-BAA JJ McArdle 3/15/07-10/1/10: Role: PI
Defense Threat Reduction Agency, Department of Defense
Therapeutic efficacy of botulinum metalloendoprotease inhibitors: Protection and recovery of neurotransmitter release and neuromuscular function
This study is a part of a collaborative effort to discover and develop antidotes to botulinum neurotoxins
Kirby Foundation E Townes-Anderson 12/1/02-12/31/11: Role: Co-PI
Synaptic Interactions: Formation and Plasticity
This study examines the effects of streptozotocin-induced diabetes on the function and morphology of the mouse neuromuscular junction