RNA- and DNA-binding protein dysfunction, interferon signaling, and neuron loss in ALS and neurodegenerative diseases 2432

Abstract Description RNA- and DNA-binding proteins are crucial for regulating gene expression by affecting DNA accessibility, transcription, and repair, as well as RNA splicing, transport, and stability. Dysfunction, mislocalization, aggregation, and liquid-liquid phase separation of these proteins are common in neurodegenerative and neuroinflammatory diseases. TDP43 mislocalization is notably implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In 97% of ALS cases, the loss of nuclear TDP43 and the formation of cytoplasmic aggregates (TDP43 proteinopathy) in motor neurons are observed. This loss or mislocalization of TDP43 disrupts nucleic acid sequestration and may activate cytosolic DNA and RNA sensors such as RIG1 and cGas-STING pathways, leading to the expression of interferon-stimulated genes (ISGs). Evidence suggests that the ubiquitin-like protein ISG15 contributes to neuron loss. Using primary murine cortical neurons, human IPSC-derived motor neurons, and mixed neural cultures, we report the impact of TDP43 knockdown and mislocalization on neuronal interferon signaling and ISG15 expression. We also use ISG15-deficient neurons to measure ISG15-dependent impacts on neuron viability. Our findings show ISG15-dependent effects on cGas-STING signaling, astrogliosis, and neuron loss in an AAV-C9orf72 mouse model of ALS using global and conditional ISG15 KO mice. Funding Sources Supported by Dominium Foundation Career Development Award (Clarkson). Topic Categories Neuroimmunology (NEUR)