Fig. 4

Inflammation in ALS. TDP-43 or SOD1 forms aggregates in the cytoplasm due to genetic and/or environmental factors, causing deleterious effects to neuron. SOD1 aggregation induces oxidative stress, while TDP-43 aggregates invade mitochondria and release mtDNA into the cytoplasm, inducing inflammation through the cGAS-STING pathway. Some mitochondria related genetic variants directly lead to dysfunction of mitochondria and oxidative stress in motor neurons. Proinflammatory cytokines and DAMPs released from damaged motor neurons activate microglia and other immune cells, leading to a persistent inflammatory attack on the motor neurons. Genetic and environment factors also promote the activation of microglia and other immune cells directly, benefiting the development of ALS