Neuromuscular junction in amyotrophic lateral sclerosis: Study of the pathological mechanisms

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by the death of upper and lower motor neurons (MN) and severe muscle atrophy. In recent years, it has been shown that the degeneration MNs can also be caused or exacerbated by other neighbouring cells such as glial cells or skeletal muscle, and these are also known as non-cell autonomous mechanisms. Regarding skeletal muscle, muscle atrophy is not a mere result of denervation, but ALS patients and animal models show intrinsic muscle defects independently of MN degeneration. Likewise, synapses between motor nerve terminals and skeletal muscle fibres occur at the neuromuscular junction (NMJ). Defects in NMJs prior to MN degeneration or symptom onset have also been widely reported in ALS, leading to the proposal of the ‘dying-back’ theory, which postulates that MN defects begin at the distal nerve terminals located in the NMJ, and are transmitted retrogradely to the MN soma, ultimately inducing its death.