A hypothetical model is presented in Figure 5, summarizing the possible molecular mechanisms involved in MN vulnerability in ALS. The regulation of synaptic plasticity and neuronal excitability may underlie susceptibility in ALS involving nuclear-cytoplasmic defects, ER stress, transport dysfunction and mitochondrial alterations. From an initial site of onset, neurodegeneration begins in susceptible MN groups, and then spreads contiguously throughout the neuroanatomy, in a defined pattern, to the surrounding cells. This therefore highlights the role of impaired neurotransmission in triggering and propagating neurodegeneration in ALS. Glial cells are involved in both the onset and progression of ALS.