Profile

Chien-Ping Ko

Professor, Section of Neurobiology
Department of Biological Sciences

Chien-Ping  Ko

Research Topics

  • Synaptic structure, function, formation, repair, and maintenance.
  • Synapse-glia interactions at the neuromuscular junction.
  • Cellular and molecular mechanisms of the pathogenesis of Spinal Muscular Atrophy (SMA).

Research Images

Neuromuscular junctions in a mammalian hindlimb muscle.  NMJs are triple-labeled to reveal axons (blue), presynaptic nerve terminals (green), and postsynaptic acetylcholine receptors (red).
Neuromuscular junctions in a mammalian hindlimb muscle. NMJs are triple-labeled to reveal axons (blue), presynaptic nerve terminals (green), and postsynaptic acetylcholine receptors (red).
Triple staining of spinal motoneurons (red) and synapses (blue and green) in the ventral horn of the spinal cords of SMA mutant mice.
Triple staining of spinal motoneurons (red) and synapses (blue and green) in the ventral horn of the spinal cords of SMA mutant mice.
The tripartite organization of vertebrate neuromuscular junctions (NMJs).  (A-D) A frog NMJ triple labeled to reveal perisynaptic Schwann cells (PSCs) (A, green), axons and presynaptic nerve terminals (B, blue), and postsynaptic acetylcholine receptors (AChRs) (C, red).  The tripartite organization is further shown in the merged image (D).  (E) Electron micrograph of an adult NMJ in cross section.  (Figure 1A-D adapted from Ko et al., 2006 In ?Biology of the Schwann cell? ed. by Armati, P. J., Cambridge University Press. In Press.  Figure 1E adapted from Reddy et al., 2003. Neuron, 40:563-580).
The tripartite organization of vertebrate neuromuscular junctions (NMJs). (A-D) A frog NMJ triple labeled to reveal perisynaptic Schwann cells (PSCs) (A, green), axons and presynaptic nerve terminals (B, blue), and postsynaptic acetylcholine receptors (AChRs) (C, red). The tripartite organization is further shown in the merged image (D). (E) Electron micrograph of an adult NMJ in cross section. (Figure 1A-D adapted from Ko et al., 2006 In ?Biology of the Schwann cell? ed. by Armati, P. J., Cambridge University Press. In Press. Figure 1E adapted from Reddy et al., 2003. Neuron, 40:563-580).
Selective ablation of PSCs causes retraction of adult nerve terminals.  (a) a low-magnification view of a cluster of NMJs, in which PSCs (with red nuclear staining of ethidium homodimer-1) are ablated with complement-mediated lysis.  (b-d) 1 week after removal of PSCs, the original PSC outlines can be visualized with peanut agglutinin (PNA) (b), while nerve terminals (c) partially retract in the absence of PSCs for ~1 week.  AChR clusters (d) appear unaffected at this duration, and match the original lengths of synaptic sites.  (e-g) NMJ ultrastructure after PSC ablation.  At a few hours after PSC ablation (e), the nerve terminal (N) is devoid of the overlying PSC, instead showing only a PSC ?ghost? consisting of basal lamina and membrane fragments.  One week later (f), PSCs remain absent from NMJs, leaving uncovered nerve terminals apposed to muscle fibers.  In some cases, nerve terminals retract, leaving a vacant space (asterisk in g) overlying the post-junctional folds.  (Figure 2 adapted from Reddy et al., 2003, Neuron, 40:563-580).
Selective ablation of PSCs causes retraction of adult nerve terminals. (a) a low-magnification view of a cluster of NMJs, in which PSCs (with red nuclear staining of ethidium homodimer-1) are ablated with complement-mediated lysis. (b-d) 1 week after removal of PSCs, the original PSC outlines can be visualized with peanut agglutinin (PNA) (b), while nerve terminals (c) partially retract in the absence of PSCs for ~1 week. AChR clusters (d) appear unaffected at this duration, and match the original lengths of synaptic sites. (e-g) NMJ ultrastructure after PSC ablation. At a few hours after PSC ablation (e), the nerve terminal (N) is devoid of the overlying PSC, instead showing only a PSC ?ghost? consisting of basal lamina and membrane fragments. One week later (f), PSCs remain absent from NMJs, leaving uncovered nerve terminals apposed to muscle fibers. In some cases, nerve terminals retract, leaving a vacant space (asterisk in g) overlying the post-junctional folds. (Figure 2 adapted from Reddy et al., 2003, Neuron, 40:563-580).

Research Overview

Among the most challenging questions in neurobiology is how synaptic connections form, function, and maintain at the appropriate targets in normal and diseased nervous systems. To address these important questions, we study the neuromuscular junction (NMJ), a model synapse due to its relatively simple morphology and easy accessibility. Using electrophysiological, morphological, and molecular approaches, we examine the role of synaptic molecules in transmitter release and synaptic plasticity in knockout mice that lack certain genes. We are also interested in the role of glial cells and glial-derived factors in the maintenance of synaptic structure and function as well as in promoting synapse development, regeneration, and sprouting. Our research on synapse-glial interactions explores an emerging concept that glial cells tell neurons to build larger, stronger, and more stable synapses.

We also use transgenic mice to study spinal muscular atrophy (SMA), the leading genetic cause of infant mortality characterized by the loss of spinal motor neurons and widespread muscle atrophy. We are studying the possible contribution of motor circuit defects to the pathogenesis of SMA, as well as the role of different cell types in SMA disease mechanisms. In addition, we are interested in translational research by testing molecules that could potentially be used to treat this devastating disorder. I co-edited with Drs. Charlotte Sumner and Sergey Paushkin a new book entitled "Spinal Muscular Atrophy: Disease Mechanisms and Therapy." San Diego: Academic Press, 2017. http://store.elsevier.com/product.jsp?isbn=9780128036853&pagename=search



Contact Information

Mailing Address University of Southern California
Department of Biological Sciences
3641 Watt Way HNB 209
Los Angeles, CA 90089-2520
Office Location HNB 209
Office Phone (213) 740-9182
Lab Location HNB 209
Lab Phone (213) 740-9179
Fax (213) 740-5687
Office Location HNB 209

Websites

Education

  • B.S., National Taiwan University, 1970.
  • Ph.D., Washington University in St. Louis, 1975.
  • Post-Doctoral, University of Colorado Medical Center, 1978.
  • Post-Doctoral, National Institutes of Health, 1981.

Selected Publications

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  • Sumner, CJ, Paushkin, S, Ko, C-P, eds. (2017), Spinal Muscular Atrophy: Disease Mechanisms and Therapy. San Diego: Academic Press. Release Date: Link
  • Osman EY, Washington CW 3rd, Kaifer KA, Mazzasette C, Patitucci TN, Florea KM, Simon ME, Ko CP, Ebert AD, Lorson CL. (2016) Optimization of Morpholino Antisense Oligonucleotides Targeting the Intronic Repressor Element1 in Spinal Muscular Atrophy. Mol Ther. doi: 10.1038/mt.2016.145. [Epub ahead of print] PubMed Link
  • Zhao X., Feng Z., Ling, K. K. Y., Mollin A., Sheedy J., Yeh S., Petruska J., Narasimhan J., Dakka A., Welch E., Karp G., Chen K.S., Metzger F., Ratni H., Lotti F., Tisdale S., Naryshkin N.N., Pellizzoni L., Paushkin S., Ko C.-P.*, Weetall M.* (2016) Pharmacokinetics, Pharmacodynamics and Efficacy of a Small Molecule SMN2 Splicing Modifier in Mouse Models of Spinal Muscular Atrophy (*equal co-corresponding authors). Human Molecular Genetics, Feb 29. pii: ddw062. [Epub ahead of print] PubMed PubMed Link
  • Zhou C, Feng Z, Ko CP. (2016) Defects in Motoneuron-Astrocyte Interactions in Spinal Muscular Atrophy.  J Neurosci. 2016 Feb 24;36(8):2543-53. doi: 10.1523/JNEUROSCI.3534-15.2016. PubMed Link
  • Shababi M, Feng Z, Villalon E, Sibigtroth CM, Osman EY, Miller MR, Williams-Simon PA, Lombardi A, Sass TH, Atkinson AK, Garcia ML, Ko CP, Lorson CL. (2016). Rescue of a Mouse Model of Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) by AAV9-IGHMBP2 is Dose Dependent.  Mol Ther. 2016 Feb 10. doi: 10.1038/mt.2016.33. [Epub ahead of print] PubMed Link
  • Feng Z, Ling KK, Zhao X, Zhou C, Karp G, Welch EM, Naryshkin N, Ratni H, Chen KS, Metzger F, Paushkin S, Weetall M*, Ko, C-P* (2016) Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset.  (*equal co-corresponding authors). Hum Mol Genet. 2016 Mar 1;25(5):964-75. doi: 10.1093/hmg/ddv629. Epub 2016 Jan 11. PubMed Link
  • Rindt H, Feng Z, Mazzasette C, Glascock JJ, Valdivia D, Pyles N, Crawford TO, Swoboda KJ, Patitucci TN, Ebert AD, Sumner CJ, Ko CP*, Lorson CL*. (2015) Astrocytes influence the severity of spinal muscular atrophy. (*equal co-corresponding authors) Hum Mol Genet. 2015 24(14):4094-102 doi: 10.1093/hmg/ddv148. Epub 2015 Apr 24. PubMed Link
  • Miller N, Feng Z, Edens BM, Yang B, Shi H, Sze CC, Hong BT, Su SC, Cantu JA, Topczewski J, Crawford TO, Ko CP, Sumner CJ, Ma L, Ma YC.(2015) Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy. The Journal of Neuroscience, 35(15):6038-50. PubMed Link
  • Ko, C.-P. and Robitaille, R. (2015) Perisynaptic Schwann cells at the neuromuscular synapse: adaptable, multitasking glial cells. In “Glia” (Ed. by B. Barres, MR Freeman, B. Stevens). Cold Spring Harbor Perspectives in Biology. Pp. 237-255. PubMed Link
  • Naryshkin N.A. et al., (2014) SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345:688-693. (Recommended by Faculty of 1000 Prime)

    PubMed Link
  • Ling, K. K. Y., Gibbs, R.M., Feng, Z., and Ko, C.-P. (2012) Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Human Molecular Genetics, 21:185-195; ddr453 first published online October 13, 2011. PubMed Link
  • Ling, K.K.Y., Lin, M.-Y., Zingg, B., Feng, Z. and Ko, C.-P. (2010) Synaptic Defects in the Spinal and Neuromuscular Circuitry in a Mouse Model of Spinal Muscular Atrophy. PLoS ONE 5(11): e15457. doi:10.1371/journal.pone.0015457 (Recommended by Faculty of 1000 Prime) PubMed Link
  • Ko, C.-P. and Thompson, W. J. (2003) We edited the special issue, The Neuromuscular Junction, in tribute to Sir Bernard Katz.  Journal of Neurocytology, 32: 421- 1037.  Link
  • Reddy, L. V., Koirala, S., Sugiura, Y., Herrera, A. A., and Ko, C.-P. (2003) Glial cells maintain synaptic structure and function and promote development of the neuromuscular junction in vivo.  Neuron, 40:563-580. (Recommended by Faculty of 1000 Biology) PubMed Link