Damage to the central nervous system irreversibly leads to a similar form of tissue lesions. Regardless of whether the injury source comes from trauma, ischemia, or neurodegeneration, the resulting CNS fibrotic lesions permanently prevent efficient tissue recovery. Consequently, most clinical manifestations of brain damage remain untreatable. Recently, brain fibroblast cells were found in various locations within the CNS and proposed to remodel cerebral vasculature, regulate immune cell activity and form the core of brain lesions. Despite the multifaceted potential of fibroblasts to control brain damage response and neurodegeneration, researchers only begin to understand the mechanisms regulating their activity. We recently found that brain fibroblasts are activated in the early stages of amyotrophic lateral sclerosis (ALS) and accelerate disease severity in patients (Månberg et al. Nature Medicine 2021). The goal of the proposed research project is to identify the molecular mechanisms of brain fibroblast activation in ALS. We will integrate single-cell and bulk cortex transcriptomics of ALS patients together with plasma profiling to identify the factors that can regulate fibroblast cell activity and become clinically relevant biomarkers and therapeutic targets. Our preliminary results from single-cell analysis indicate that activated brain fibroblast cells in ALS patients’ cortex develop several trajectories of differentiation which likely represent their multifaceted functions. Since the fibrotic hardening of the CNS lesions – commonly referred to as “sclerosis” - is widely-represented in multiple forms of brain injury and neurodegeneration, the insights of our study can provide potential therapeutic strategies that are translatable into multiple forms of neuropathy.