Contributions of Iron Regulatory Proteins and Ferroptosis to Neurodegeneration

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1 Project Summary 2 Levels of redox active iron accumulate during both normal aging and neurodegenerative disease progression. Thus, 3 strategies for mitigating iron-mediated cellular damage could be used to promote healthy aging and protect against 4 neurodegenerative decline. One such approach may be through the prevention of ferroptosis, a form of iron-mediated 5 programmed cell death. However, we must first understand how cells manipulate the homeostatic regulators of iron 6 metabolism to contribute to disease before we can fully develop iron-targeted therapeutic strategies. The iron regulatory 7 proteins 1 and 2 (IRP1 and IRP2) are the master regulators of intracellular iron homeostasis because they coordinate the 8 expression of proteins involved in iron storage, uptake, and efflux. Yet, the roles and regulation of IRPs during cellular 9 ferroptosis remain unknown. The long-term goal of the Montgomery lab is to understand how acquisition of exaggerated 10 amounts of iron promote metabolic perturbations that lead to iron-mediated disease progression. The primary objective 11 of this work is to establish how IRP mRNA binding activity influences cellular sensitivity to ferroptotic cell death. The 12 central hypothesis is that increased IRP mRNA binding activity promotes cellular iron accumulation and facilitates 13 ferroptotic cell death. To test this hypothesis, in Aim 1, we will utilize primary neurons isolated from zebrafish injected 14 with IRP1 and IRP2 morpholinos to assess IRP-dependent differences in susceptibility to ferroptotic cell death. 15 Intriguingly, pathologically modified tau can also inhibit iron efflux, and the resulting iron accumulation has been 16 associated with neuronal ferroptosis and dementia progression, but the role of IRPs in ferroptosis and tau-mediated 17 neurodegeneration remains undefined. Thus, in Aim 2, we will utilize a zebrafish model of tauopathy determine the extent 18 to which ferroptosis inhibition protects against neurodegeneration in and IRP-dependent manner. Such studies are 19 important because uncontrolled activation of ferroptosis can further exacerbate neurodegeneration in tau-mediated 20 pathologies such as Alzheimer’s disease and related dementias (ADRD). Thus, findings from this work could lead to 21 improved therapeutic strategies for mitigating iron associated ADRD risks and improving ADRD patient outcomes.