department of Pharmacology, Physiology & Neuroscience
Joseph J. Mc Ardle, Ph.D.
Joseph J McArdle joined the NJMS in 1972 after completing PhD and postdoctoral studies in Cellular Neuropharmacology at the State University of New York at Buffalo. His work in synapse development, pathophysiology, and pharmacology has grown as a result of sabbatical leaves with Alberto Mallart (CNRS), Peter W Gage (Australian National University), Phillip Nelson (NIH), and Veit Witzemann (Max-Planck Institute for Medical Research). This work utilizes target-selective neurotoxins as well as transgenic mice to discover the function(s) of proteins that are essential to synapse development and health. The work focuses on the neuromuscular junction because of the rich knowledge of the molecular basis of normal transmission across this model synapse. Dr. McArdle's work extends this knowledge to mouse models of diseases that target molecules critical to synaptic transmission; e.g., diabetic neuropathy, ALS, botulism, myasthenia gravis. McArdle has extended the techniques and concepts related to neuromuscular junction research to studies of cardiac arrhythmias as well as the molecular action of addictive drugs. Numerous scholars have studied in McArdle's laboratory including postdoctoral fellows (approximately 11), as well as PhD (12) and Masters (6) students. The work from McArdle's lab is presented in more than 100 peer reviewed articles. McArdle served on review panels of the NSF and NIH and continues to review grants applications as well as scientific manuscripts.
Ph.D., 1971, State University of New York at Buffalo
|Garcia, CC, JG Potian, K Högnason, B Thyagarajan, L. G. Sultatos, N Souayah, VH Routh, and JJ McArdle. 2012. Acetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in experimental type I diabetic neuropathy. American J Physiology Endocrin Metab 303: doi:10.1152/ajpendo.00622.2011.|
|Chevessier, F, C Peter, U Mersdorf, E Girard, E Krejci, JJ McArdle, and V Witzemann. 2012. A new mouse model for the slow-channel congenital myasthenic syndrome induced by the AChR eL221F mutation. Neurobiol Disease 45: 851-861. doi: 10.1016/j.nbd.2011.10.02476.|
|Souayah, N, KM Coakley, R Chen, N Ende, and JJ McArdle. 2012. Defective neuromuscular transmission in the SOD1G93A transgenic mouse improves after administration of human umbilical cord blood cells. Stem Cell Reviews and Reports 8: 224-228. DOI: 10.1007/s12015-011-9281-3|
|Ho, MF, M Pires-Alves, L Chang, B Thyagarajan, JE Bloom, Z Gu, KK Aberle, JJ McArdle, and BA Wilson. 2010. Recombinant Botulinum Neurotoxin A Heavy Chain-based Delivery Vehicles for Neuronal Cell Targeting. Protein Engineering, Design and Selection, doi: 10.1093/protein/gzq093|
|Potian, JG, B Thyagarajan, K Hognason, FJ Lebeda, JJ Schmidt, M Adler, and JJ McArdle. 2010. Investigation of ‘CRATKML’ derived peptides as antidotes for the in vivo and in vitro paralytic effect of botulinum neurotoxin A. The Botulinum J., Vol 1, No. 4: 407-417.|
|Pacifici, PG, P Christoph, P Yampolsky, M Koenen, JJ McArdle, and V Witzemann. 2011. Novel mouse model reveals distinct activity-dependent and –independent contributions to synapse development. PLOS One 6: 1-13.|
|Thyagarajan, B, CC Garcia, JG Potian, K Hognason, K Capková, ST Moe, AR Jacobson, KD Janda, and JJ McArdle. 2010. Small molecule hydroxamate metalloendoprotease inhibitors antagonize the acute paralytic action of botulinum neurotoxin A. Neuropharmacology 58: 1189-1198. doi:10.1016/j.neuropharm.2010.02.014|
|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.|
|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.|
|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|
Areas of Interest
Pre- and postsynaptic alterations in response to autoantibodies to muscle specific tyrosine kinase
The profound muscle weakness of myasthenia gravis (MG) derives from a reduced safety for transmission across the neuromuscular junction (NMJ). Mutations of, or auto-antibodies to, key NMJ proteins reduce the safety factor for transmission across the NMJ. As a result, the muscle response to motor nerve excitation declines with concomittant weakness of respiratory and limb muscles. Muscle specific tyrosine kinase (MuSK)is a NMJ protein that is central to formation and longterm health of the muscle postsynaptic, or endplate, membrane. Patients with altered MuSK suffer severe MG. Because MuSK-MG is refractory to conventional therapies for MG, our lab works to discover novel therapies for MuSK-MG. To do this, we study a mouse model of autoimmune MuSK-MG. Our search is built upon experiments to test two fundamental hypothesis. Testing of these hypotheses will not only achieve the essential goal of new therapies for MuSK-MG, but also further fundamental understanding of trophic signalling between nerve and muscle. In order to further understand the clinical relevance of trophic interactions between nerve and muscle, our lab also studies the NMJ during diabetes, ALS, and botulism. In studies performed parallel to the MuSK studies summarized above, we discovered that diabetes alters a key protein of the NMJ. Furthermore, ALS and botulinum neurotoxin A similarly alter nerve terminal function. Thus, our studies of MuSK-MG, diabetic neuropathy, ALS, and botulism are uncovering common pathways in the pathobiology of NMJ dysfunction. All chemical synapses have proteins that are homologus to those at the NMJ. Therefore, the discovery of functional and trophic roles of these proteins at the NMJ has fundamentally important implications for understanding the basis of synapse health as well as treating synapse-related disease.