Figure 1

ALS is caused by interplay of various molecular pathways in motor neurons and an interaction with neighbouring non-neuronal cells like microglia and astrocytes. Microglial cells activate an inflammatory cascade via secretion of cytokines. Astrocytes lead to motor neuron injury through release of inflammatory mediators such as nitric oxide and prostaglandin E2. Accumulation of superoxide radicals and oxidative stress, aberrant RNA processing, protein misfolding and insoluble proteins may cause motor neuron degeneration in ALS. Protein aggregation may lead to endoplasmic reticulum stress along with defective endosomal trafficking and mitochondrial damage, which may cause organelle disruption and activates autophagy and apoptotic pathways. Axonal transport abnormalities lead to energy deficiency in the axon along with the defective axonal growth and axonal dysfunction. Axonal dysfunction, defective angiogenesis and metabolic disturbance may contribute to motor neuron degeneration in ALS.