Figure 1.0: A Neuregulin 1 (NRG 1) feedback loop between neurons and non-neuronal cells
Figure 2.0: Increased NRG1 receptor activation on activated microglia in the lateral corticospinal tracts and ventral horn of ALS patients
We utilize an integrated approach (combining molecular biology, cell biology, and immunology methods) to address the complexity of motor neurons/microglia as well as the NRG1/BDNF interaction in human ALS and the superoxide dismutase 1 (SOD1) mice. By understanding the detailed signaling pathway from NRG1 production, diffusion, and microglial activation in a neurodegenerative disease condition, we have potentially identified NRG1 receptor activated (phosphorylated erbB receptor) microglia from early disease onset to later progression that may relate to local motor neuron/axon degeneration in the ALS mouse superoxide dismutase 1 (SOD1) model and also in human ALS autopsy tissue. As ALS is a heterogeneous disease in patients, our goal is to develop cell-specific and personalized therapeutic targets to treat ALS patients.
We have also developed a novel, humanized fusion protein that targets heparin-rich surfaces using NRG1’s heparin-binding domain fused to a decoy NRG1 receptor, called HBD-S-H4. This drug effectively blocks microglial activation in vivo. Our early results suggest that long-term intraventricular infusion of this antagonist slows disease progression and prolongs survival of SOD1 mice without any obvious signs of toxicity.
Current Research Interests in Amyotrophic Lateral Sclerosis (ALS)
- What is the relationship between upper and lower motor neuron disease progression?
- Where does each start and how do they spread?
- Does microglial activation represent a common, causal role in disease progression, both in the ventral horn and in the corticospinal tracts?
- Compare the brain and the spinal cord pathology of human ALS and SOD1 mice.
- Identify a common therapeutic target in ALS patients and SOD1 mice.
- Investigate the mechanisms of NRG1 signaling in ALS patients and SOD1 mice.
- Test therapeutic potential of blocking inflammatory microglial activation using NRG1 agonist and antagonist in SOD1 mice.
Current Research Interests in Multiple Sclerosis (MS)
- Compare the brain and spinal cord pathology of human MS and its animal models, including experimental autoimmune encephalomyelitis (EAE) and cuprizone demyelination models.
- Identify common therapeutic targets in MS patients and its animal models.
- Investigate the mechanisms of inflammatory microglial activation in MS patients and EAE/cuprizone models.
- Test therapeutic potential of blocking inflammatory microglial activation in EAE/cuprizone models.
- Wang, J., Hmadcha, A., Zakarian, V., *Song, F., and Loeb, J.A. Rapid transient isoform-specific neuregulin1 transcription in motor neurons is regulated by neurotrophic factors and axon-target interactions, Mol Cell Neurosci. 68:73-81, 2015.
- Dachet, F., Bagla, S., Keren-Aviram, G., Norton, A., Balan, K., Saadat, L., Valyi-Nagy, T., Kupsky, W., Song, F., Dratz, E., and Loeb, J.A. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering, Brain. 138(Pt 2):356-70, 2015.
- *Song, F., Chiang, P., Ravits, J., and Loeb, J.A. Activation of microglial neuregulin1 signaling in the corticospinal tracts of ALS patients with upper motor neuron signs. Amyotroph Lateral Scler Frontotemporal Degener. 15:77-83, 2014.
- *Song, F., Bandara, M., Deol, H., Loeb, J.A., Benjamins, J., and Lisak, R. Complexity of trophic factor signaling in experimental autoimmune encephalomyelitis due to differential expression of neurotrophic and gliotrophic factors. J Neuroimmunol. 262:11-8, 2013.
- *Song, F., Chiang, P., Wang, J., Ravits, J., and Loeb, J.A. Aberrant neuregulin 1 signaling in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 71:104-15, 2012.
- Ma, Z., Wang, J., Song, F., and Loeb, J.A. Critical period of axoglial signaling between neuregulin-1 and brain-derived neurotrophic factor required for early Schwann cell survival and differentiation. J Neurosci. 31:9630-40, 2011.
- *Song, F., Wardrop, R., Gienapp, I., Stuckman, S., Meyer, A., Shawler, T., and Whitacre, C.C. The Peyer’s patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomylelitis (EAE). J. Autoimmunity. 30:230-237, 2008.
- *Song, F., Guan, Z., Gienapp, I., Shawler, T., Benson, J., and Whitacre, C.C. The thymus plays a role in oral tolerance in experimental autoimmune encephalomyelitis (EAE). J. Immunology, 177:1500-1509, 2006.
- Song, F., Gienapp, I., Wang, X., and Whitacre, C.C. Activation of Vb8 T cells affects spontaneous EAE in MBP TCR transgenic mice. J. Neuroimmunology, 123:112-122, 2002.
- Song, F., Wardrop, R., Gienapp, I., Stuckman, S., Goverman, J., and Whitacre, C.C. Differences between two strains of myelin basic protein (MBP) TCR transgenic mice: implications for tolerance induction. J. Autoimmunity, 18:27-37, 2002.
- Song,F., & Whitacre, C.C. The role of the gut lymphoid tissue in induction of oral tolerance. Current Opinion in Investigational Drugs, 2:1382-6, 2001.