Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that primarily affects motoneurons in the brain and spinal cord. Astrocyte and microglia activation as well as skeletal muscle atrophy are also typical hallmarks of the disease. However, the functional relationship between astrocytes, microglia and skeletal muscle in the pathogenic process remains unclear. Here, we report that the tumor necrosis factor-like weak inducer of apoptosis (Tweak) and its receptor Fn14 are aberrantly expressed in spinal astrocytes and skeletal muscle of SOD1G93A mice. We show that Tweak induces motoneuron death, stimulates astrocytic interleukin-6 release and astrocytic proliferation in vitro. The genetic ablation of Tweak in SOD1G93A mice significantly reduces astrocytosis, microgliosis and ameliorates skeletal muscle atrophy. The peripheral neutralization of Tweak through antagonistic anti-Tweak antibody ameliorates muscle pathology and notably, decreases microglial activation in SOD1G93A mice. Unexpectedly, none of these approaches improved motor function, lifespan and motoneuron survival. Our work emphasizes the multi-systemic aspect of ALS, and suggests that a combinatorial therapy targeting multiple cell types will be instrumental to halt the neurodegenerative process.