Dr. Song’s lab studies the pathology and therapeutics of ALS by focusing on the interaction between neuron and non-neuronal cells (Figure 1.0). The overall hypothesis is that soluble forms of neuregulin 1 (NRG1, a gliotrophic factor) are naturally released from the ongoing neurodegeneration of motor neurons/axons in ALS, promoting localized inflammatory microglial activation. This activation may produce potent neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which together with NRG1 results in localized motor neuron/axon degeneration and the degeneration spreads throughout the ventral horn and the corticospinal tracts (Figure 2.0).
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.