Non-cell autonomous toxicity in neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), involves damage in multiple cell types, not just neurons. While traditionally viewed as cell-autonomous, recent evidence shows that mutations in ubiquitously expressed genes like SOD1 cause disease through interactions with non-neuronal cells. In ALS, mutant SOD1 causes various toxic mechanisms, including excitotoxicity, ER stress, proteasome inhibition, mitochondrial damage, extracellular toxicity, and microglial activation. These mechanisms contribute to the selective vulnerability of motor neurons. Similarly, non-cell autonomous mechanisms are observed in other neurodegenerative diseases like Huntington's disease, Parkinson's disease, prion diseases, spinocerebellar ataxias, and Alzheimer's disease. In these diseases, damage to non-neuronal cells such as astrocytes, microglia, and Schwann cells contributes to disease progression. The convergence of damage in multiple cell types explains the selective neuronal vulnerability in these disorders. Understanding these non-cell autonomous mechanisms is crucial for developing effective therapies.Non-cell autonomous toxicity in neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), involves damage in multiple cell types, not just neurons. While traditionally viewed as cell-autonomous, recent evidence shows that mutations in ubiquitously expressed genes like SOD1 cause disease through interactions with non-neuronal cells. In ALS, mutant SOD1 causes various toxic mechanisms, including excitotoxicity, ER stress, proteasome inhibition, mitochondrial damage, extracellular toxicity, and microglial activation. These mechanisms contribute to the selective vulnerability of motor neurons. Similarly, non-cell autonomous mechanisms are observed in other neurodegenerative diseases like Huntington's disease, Parkinson's disease, prion diseases, spinocerebellar ataxias, and Alzheimer's disease. In these diseases, damage to non-neuronal cells such as astrocytes, microglia, and Schwann cells contributes to disease progression. The convergence of damage in multiple cell types explains the selective neuronal vulnerability in these disorders. Understanding these non-cell autonomous mechanisms is crucial for developing effective therapies.