Fig. 2

Non-cell-autonomous mechanisms of motor neuron loss in ALS. Non-cell-autonomous mechanisms within the motor cortex and spinal cord which contribute to motor neuron loss. The combined effects of microglial-derived cytokines, astrocyte-induced toxicity, NK cell cytotoxicity and macrophage phagocytosis of degenerating axons all need to be controlled. In addition, in the periphery, IL-6 and Activin A combine to induce disruption of the neuromuscular junction with consequent axonal die back due to loss of trophic support. Finally, chronically increased activated STAT3 contributes to motor neuron dysfunction through many of the processes summarised in Table 2. These mechanisms are reviewed in more detail below. ActA, activin A; SMAD2,3, mothers against decapentaplegic transcription factors 2 and 3; NMJ, neuromuscular junction; NK, natural killer; TNF, tumor necrosis factor; NFκB, NF-kappa-B; IL1/6, interleukin 1/6