Resolving the Role of Neuronal STING in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

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Project Summary: The stimulator of interferon genes (STING) pathway is responsible for sensing DNA damage and activating the innate immune response as part of a host pathogen defense program. Although STING has been implicated in several neurodegenerative diseases, the effect has thought to be mediated through myeloid cells, and the potential for STING activation within neurons has been not explored. The main goal of this proposal is to define the role of neuronal STING in neurodegeneration and dementia using amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in response to DNA damage. We will focus on the intronic hexanucleotide repeat in the C9orf72 gene, which is the most common familial cause of both ALS and FTD, and TDP-43, which aggregates in almost all ALS cases and about half of FTD. The overall model is that DNA damage, which can be caused by C9orf72 dipeptides as well as TDP-43 dysfunction, leads to STING activation in neurons. Our preliminary data present a concordant picture of increased neuronal STING in human C9orf72 brains, mouse C9orf72 models, and human induced pluripotent stem cell (iPSC)-derived neurons from ALS individuals. We will determine the regional specificity of STING increase and how it correlates with neurodegeneration, DNA damage, and other C9orf72 and TDP-43 disease features. To test the consequence of STING in neurons, we will use an AAV-based C9orf72 disease model and determine whether neuronal-specific knockout of STING affects neurodegeneration and how the effect compares to global knockout of STING or knockout within microglia. Using iPSC-derived and primary mouse neurons, we will determine mechanisms of STING activation, and how activation ties to downstream modulators within vulnerable neuronal subtypes. We will also assess to what extent blocking or knocking down STING protects neurons against disease mechanistic models in vitro. The successful completion of the project sets the stage for validating specific targets for therapeutic intervention, evaluating key pathway components as disease biomarkers, and investigating STING pathways in other neurodegenerative diseases and dementias.