Diverse pathogenic processes contribute to neurodegeneration, but there are currently no disease-reducing treatments available to slow the onset or progression of FTD or related disorders. New treatment strategies based on novel targets are essential for realizing this critical need. Mitochondria produce energy but they also release damaging free radicals that promote oxidative stress and neural impairments, and may contribute to FTD and related dementias. Indeed, accumulation of mitochondrial free radicals is likely a main driver of progressive neuronal deficits, aberrant protein accumulation, and brain inflammation in disease. However, current genetic and pharmacologic tools to block mitochondrial free radicals invariably affect metabolism and disrupt cellular signaling, and therefore have limited clinical efficacy. The proposed research may offer a promising new approach to FTD treatment due to the unique mechanism of action and disease-modifying properties of newly discovered class of compounds targeting mitochondrial free radicals. Based on our results in experimental models of FTD-linked pathology, this new class of compounds may represent an effective strategy for reducing neurodegeneration and brain inflammation that is causally linked to free radicals. We will design novel therapeutic molecules based on this new class of compounds with the goals of optimizing their drug-like properties and enabling intellectual property protection for medicinal development. These studies are expected to identify novel molecules for potentially treating FTD and related disorders of the brain. If successful, our project would open an exciting new front in the strategic fight against FTD.