Mechanisms of renin-angiotensin signaling in programmed and insult-induced neuronal death

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PROJECT SUMMARY An important goal in neuroscience is to elucidate with cellular and molecular clarity how neurodegeneration (ND) might occur in vivo, given the intricate signaling and interactions among neurons and glia in the brain. This application aims to understand a fundamental G Protein Coupled Receptor (GPCR) signaling pathway in both programmed neuronal death (PND) and insult-induced ND (IND). IND will be studied in in the context of Gaucher disease (GD), a multisystemic disorder including neuropathology before the age of three and Parkinson’s disease (PD). It is well known that neuronal death occurs both in development and in diseased conditions. During development, PND is critical for constructing a functional nervous system, e.g. by providing signals for the colonization of microglia. On the other hand, IND due to injury or disease processes significantly impairs the nervous system function. Studies employing invertebrate model organisms have provided insights. How PND and IND are mechanistically regulated in vertebrates, however, is not well understood. Through an unbiased whole organism-based small molecule screen employing a chemo-genetic nitroreductase/metronidazole (NTR/MTZ) dopamine (DA) neuron degeneration model in zebrafish, we have uncovered inhibitors of the renin-angiotensin system (RAS) that significantly protect neurons from both PND and IND. RAS is a peptidergic GPCR signaling system found in vertebrates, classically known to regulate blood pressure and salt retention. RAS inhibitors are widely used drugs for treating high blood pressure. The mechanism of action of RAS in ND however remains poorly understood, despite that RAS expression is detected in both neurons and glia, and altered expression is observed during aging, in multiple ND diseases, and inhibitors of RAS are in clinical trials for treating ND. We further find that inhibiting RAS signaling reduces DA ND in GD. Microglial colonization in the healthy developing brain is also significantly decreased upon RAS inhibition. Built on these preliminary data, we hypothesize that RAS signaling regulates both PND and IND outside its conventional role in the vascular system but involves neurons and glia. This hypothesis will be tested in both PND and IND, using a combination of molecular genetic, chemical genetic, and advanced microscopic imaging methods. Expected outcomes and impact: Through a systematic screen, we have uncovered a role of RAS signaling in both PND and IND in a highly accessible vertebrate model organism. The proposed research will create new fundamental knowledge to address the underlying mechanisms. Inhibitors of RAS signaling have clinical implications for treating ND diseases. By addressing the mechanisms of action for these agents, our research is well in line with NIH’s strategic plan to benefit human health through basic science research.