Immune Molecules Regulate Medulloblastoma and Neuronal Apoptosis

Knight, Elizabeth R.

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March 19, 2019

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Knight, Elizabeth R.
- Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum

Abstract

While the brain has long been considered an immunoprivileged region, recent research reveals that immune genes play important roles in neurons and the nervous system. Neurons not only express immune genes but these genes can serve immune or neuron-specific functions. Additionally, cytokines produced by immune cells can influence neuronal characteristics and survival. In this work, I investigated the role of an immune cytokine, interferon-gamma (IFN-γ), on neuronal apoptosis and the role of an immune gene, ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain), in cancer of the cerebellum. While IFN-γ induces apoptosis in many cell types to limit the spread of infection, here we show that it protects sympathetic neurons from death with NGF deprivation or pan-kinase inhibition. Specifically, we determined that IFN-γ inhibited apoptosis at the point of mitochondrial permeabilization, yet did not induce expression of a number of proapoptotic genes in sympathetic neurons that are upregulated in other cell types. The ability of IFN-γ to promote sympathetic neuronal survival while inducing pro-death pathways in pathogens is likely a physiologically important mechanism which could ensure the long-term survival of these neurons during critical situations of infection. We also examined the function of another immune gene, ASC, in the context of brain development and medulloblastoma, the most common malignant pediatric brain cancer. ASC exerts pro-death effects in several cell types, is silenced in many cancers, and acts as a tumor suppressor in colon cancer. Here, we present the unexpected findings that ASC deficiency robustly suppressed tumor incidence, delayed age of tumor onset, reduced premalignant lesion size, decreased EGL (external granule layer) proliferation, and increased TGF-β pathway expression and signaling in a mouse model of medulloblastoma. These results identify a critical function of ASC in driving proliferation and tumorigenesis in this medulloblastoma model. Therapies targeting ASC may be a promising strategy for preventing tumor progression of this challenging disease. Together, these studies illustrate the ability of immune genes and signals to exert powerful effects on neuronal apoptosis and on a cancer of the nervous system.

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