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