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Sung Ok Yoon

Associate Professor

Ph.D.: Tufts University Medical School
Post-doctoral Training: Cornell University
Medical College: Columbia University

134 Rightmire Hall
1060 Carmack Road
Columbus, OH 43210

Phone: 614-292-8542
Fax: 614-292-5379
E-mail: sung.yoon@osumc.edu

Current Projects

JNK3 as an integral component for the progression of Alzheimer’s disease pathology: P75 expression is often upregulated under pathological conditions, such as CNS axotomy. Under such conditions, p75 activates the brain-enriched JNK isoform, JNK3. We have been investigating the role of JNK3 under CNS pathology, discovering its mode of action in spinal cord injury, cortical axotomy, and Alzheimer’s disease. In an aggressive mouse model of Alzheimer’s disease, 5XFAD, JNK3 activation appears essential for disease progression, wherein deleting JNK3 resulted in ~90% reduction in Ab42 peptide levels. We are currently testing brain penetrant orally viable JNK3 inhibitors for their potential as therapeutic agents in Alzheimer’s disease using mouse models. Another important finding from this study was that Ab42 peptide inhibits mTOR-dependent translation, thereby perturbing normal metabolic homeostasis.  We are thus actively pursuing the role of metabolic disruption in Alzheimer’s disease pathology.

1. Harrington, A. W., Kim, J. Y., and Yoon, S.O. 2002.  Activation of Rac GTPase by p75 is necessary for JNK-mediated apoptosis in oligodendrocytes. J. Neurosci. 22: 156-166.

2. Li, Q.M., Tep, C., Yune, T.Y., Zhou, X.Z., Uchida, T., Lu, K.P., and Yoon, S.O. 2007. Regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J. Neurosci. 27: 8395-8404. PMCID: pmc3401937

3. Yoon, S.O., Park, D.J., Ryu, C. H., Ozer, H. G., Tep, C., Shin, Y.J., Lim, T.H., Pastorino, L., Kunwar, A.J., Walton, J.C., Nagahara, A.H., Lu, K.P., Nelson, R.J., Tuszynski, M.H., Huang, K., and 2012. JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron, 75: 824-837.

4. Salvucci, O., Ohnuki, H., Maric, D., Hou, X., Li, X., Yoon, S.O., Segarra, M., Eberhart, C.G., Acker-Palmer, A., and Tosato, G. 2015. EphrinB2 controls vessel pruning through STAT1-JNK3 signaling. Nat. Communications, 6: 6576

5. Liu, C., Zhang, C.W., Zhou, Y., Wong, W.Q., Lee, L.C., Ong, W.Y., Yoon, S.O., Hong, W., Fu, X.Y., Soong, T.W., Koo, E.H., Stanton, L.W., Lim, K.L., Xiao, Z.C., Dawe, G.S. APP upregulation contributes to retinal ganaglion cell degeneration via JNK3. 2017. Cell Death and Differentiation. In Press.

Drug discovery for Alzheimer’s disease with JNK3-selective, brain penetrating small molecule(s) that are orally bioavailable: Our data suggest a model wherein JNK3 is cyclically activated as the primary summing node of multiple positive feedback paths in Ab peptide signaling. Initially, JNK3 phosphorylates APP to induce rapid endocytosis and processing to produce pathological Ab42. Ab42 then induces translational block by activating AMP-activated protein kinase (AMPK), which leads to ER stress, which further activates JNK3, thereby establishing a positive feedback loop. These data suggest that blocking JNK3 activation at any point can potentially halt or slow the subsequent progression of the disease. We are currently developing an orally bioavailable JNK3-selective small molecule inhibitor that can cross the blood brain barrier efficiently.

Understanding the role of metabolic dysfunction in Alzheimer’s disease pathology: Another important finding in Yoon et al. (3) was that pathologic amyloid beta disrupts metabolic homeostasis in healthy neurons in culture. In further support, we found that new protein synthesis is significantly reduced in 5XFAD mice compared to controls, and the extent of reduction becomes greater upon treating mice with a high-fat diet. The reduction in new protein synthesis is the greatest in the hippocampus, suggesting that metabolic dysfunction may precede or correlate with cognitive decline.

(A) Identification of metabolic biomarkers for Alzheimer’s disease and development of lab-on-a-chip for their detection: Our preliminary longitudinal metabolomics study using serum and urine from 5XFAD mice identified a potential dysfunction in the glycolytic pathway at the disease onset. In support, we found aberrant activation of pyruvate kinase M2 (PKM2) in microglia in these mice. Our goal is to identify aging- or AD-specific metabolites, validate them using human serum or CSF samples, and develop a lab-on-a-chip to detect the metabolite. This project is in collaboration with a chemist in metabolomics study and a biomedical engineer.

(B) Role of PKM2 activation in Alzheimer’s disease: We found that PKM2 is mainly activated among microglia in 5XFAD mice. We are examining the role of PKM2 activation in microglia in AD mice using conditional knockout strategies.

(C) Understanding the connection between AD and another metabolic disease, type 2 diabetes (T2D): It is known that patients with type 2 diabetes (T2D) are twice as likely to develop Alzheimer’s disease when old, suggesting there may be a common mechanism that contributes to Alzheimer’s disease pathology. Although it is possible that T2D-associated pathology merely exacerbates a mechanism unique to Alzheimer’s disease, the possibility is enticing that one or more common mechanisms exist, while none is known to date.

T2D is characterized as exhibiting resistance to both insulin and leptin with hyperglycemia. We found that 5XFAD mice develop leptin but not insulin resistance by 6 months of age even on normal chow. They do develop insulin resistance at this age if fed a high-fat diet. These results suggest that a mechanism that underlies leptin resistance may be shared between Alzheimer’s disease and T2D at least in mouse models. A possible candidate is the mechanism by which AMPK is activated, while leptin inhibits it in the hypothalamus.

Along these lines, we discovered that JNK3 might be involved in regulating AMPK activation in the hypothalamus. Deleting JNK3 from 5XFAD mice restored leptin sensitivity at 6 month and AMPK activity is significantly reduced in JNK3 null mice: ghrelin failed to activate hypothalamic AMPK and AMPK-dependent phosphorylation of Raptor, an AMPK substrate, was significantly reduced in JNK3 null mice. In further support, we found that JNK3 phosphorylates the a subunit of AMPK at S356 in vitro. We have generated S356A knock-in mice both in AMPKa and a2, and are in the process of analyzing their phenotype.

1. Yoon, S.O., Park, D.J., Ryu, C. H., Ozer, H. G., Tep, C., Shin, Y.J., Lim, T.H., Pastorino, L., Kunwar, A.J., Walton, J.C., Nagahara, A.H., Lu, K.P., Nelson, R.J., Tuszynski, M.H., Huang, K., and 2012. JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron, 75: 824-837.

Role of proNGF and p75 signaling in loss of bladder control after spinal cord injury: Loss of bladder control is a challenging outcome facing spinal cord injured patients. Our data illustrate that systemic blocking of proNGF signaling through p75 with a CNS-penetrating small molecule p75 inhibitor resulted in significant improvement in bladder function after spinal cord injury (SCI) in mice. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase+ fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompanies SCI was largely prevented. Urothelial cell loss that precedes hyperplasia was solely dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and ensuing hyperplasic response was beneficial to functional recovery. Deleting p75 from the urothelium prevented urotheial death, but resulted in worsening of bladder function after SCI. These results unveil a dual role of proNGF-p75 signaling in the bladder function under pathological conditions with a CNS effect overriding the peripheral one.

1. Beattie, M.S., Harrington, A. W., Lee, R., Kim, J. Y., Boyce, S.L., Longo, F.M., Bresnahan, J.C., Hempstead, B. L., and Yoon, S.O. 2002. Pro-NGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36: 375-386.

2. Harrington, A.W., Leiner, B., J., Blechschmitt, C., Yan, Q., Welcher, A.A., Meyer, M., Arevalo, J.C., Hempstead, B.L., Yoon, S.O.*, and Giehl, K*. 2004. Secreted proNGF as the in vivo pathophysiological ligand for p75 after CNS axotomy. Proc. Natl. Acad. Sci., 101: 6226-6230 *co-corresponding author

3. Tep, C., Lim, T.H., Ko, P.O., Getahun, S., Goettl, V.M., Massa, S., Basso, M., Longo, F.M., Yoon, S.O. 2013. Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury. J. Neurosci., 33: 397-410.

4. Ryu, J.C., Tooke, K., Malley, S.E., Soulas, A., Weiss, T., Ganesh, N., Saidi, N., Daugherty, S., Saragovi, U., Ikeda, Y., Zabbarova, I., Kanai, A.J., Yoshiyama, M., Farhadi, H.F., de Groat, W.C., Vizzard, M.A., and Yoon, S.O. 2018.  Role of proNGF-p75 signaling in bladder dysfunction after spinal cord injury. Journal of Clinical Investigation, In Press.

Novel role of p75 in nociception: Loss of p75 neurotrophin receptor in global knockout mice (p75KO) results in reduced heat sensitivity. This phenotype has been mainly attributed to a ~30% loss of sensory neurons from the dorsal root ganglia (DRG) during development, which was supported by a 2-3 fold decrease in NGF sensitivity of p75KO sensory neurons, when they are cultured in isolation without Schwann cells. In addition, the p75KO mice exhibit hypomyelination in the periphery, having thinner myelin sheaths around the axons. This phenotype is presumed to be the result of losing the receptor in Schwann cells. P75 is, however, expressed by both sensory neurons and Schwann cells; to better understand the role of p75 in these two cell types, we generated conditional knockout mice lacking p75 in Schwann cells or in neurons.

Upon deleting p75 selectively in sensory neurons (Thy1-cre:p75fl/fl) or Schwann cells (Dhh-cre: p75fl/fl), we found no significant difference in myelin thickness, suggesting that the hypomyelination is likely the result of losing p75 in both cell types. Surprisingly, we also discovered that p75 in Schwann cells contributes to nociceptive behavior: Dhh-cre: p75fl/fl mice exhibited decreased heat sensitivity to the same extent as Thy1-cre:p75fl/fl mice. These unexpected results are reminiscent of a report that demonstrated nociceptive defects due to a loss of sensory neurons, upon blocking ErbB receptor signaling or FGF receptor signaling in non-myelinating Schwann cells.  Indeed, our preliminary data illustrate that BDNF addition leads to activation of ErbB2 in Schwann cells, primarily due to a novel interaction between p75 and ErbB2. Furthermore, there was a 30% loss of sensory neurons in adult Dhh-cre: p75fl/fl mice. These results reveal a novel role for p75 in regulating sensory neuron survival through its function in Schwann cells.

1. Rose Follis, Chhavy Tep, Thiago Mattos, Mi Lyang Kim, Jae Cheon Ryu, Jonah R. Chan, Ned Porter, Bruce D. Carter, and Sung Ok Yoon. Metabolic control of sensory neuron survival by p75 in Schwann cells. In Preparation.