excessive glutamatergic or reduced inhibitory influence on motor neurons leading to over-stimulation

evidence from CSF, mouse models, transcranial magnetic stimulation and neuroimaging studies

anti-glutamatergic drug riluzole has small disease-slowing effect

uniquely long motor neurons

evidence from cell culture studies and rare mutations in axonal transport genes, eg DCTN1

high energy requirements of motor neurons

evidence from mutations in SOD1-based mouse models and cell culture

microglial infiltrates seen post-mortem human MND and ­pre-symptomatic mouse models

in vivo evidence from microglial PET of human MND brain

abnormal mitochondria seen in post-mortem human MND

association of SOD1 and TDP-43

altered neurophysiological properties in mouse and cell cultures

some genes linked to MND have key RNA processing roles, eg TARDBP, FUS, or have been associated with abnormal cellular RNA foci, eg C9orf72

apparent stages of stereotyped pathological spread seen in post-mortem human MND brains

evidence of shared motor and frontotemporal networks in MND and FTD from advanced MRI

emerging theory of prion-like spread of pathology through network connections of the brain and templated protein mis-folding and aggregation

the cytoplasmic aggregation of TDP-43 that characterises nearly all cases of MND may be promoted by aberrant nuclear membrane transport