Table 2.

Molecular pathogenic themes in the syndrome of MND^4,5,24,28

Theme	Comments and broad basis
Excitotoxicity	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
Axonal transport	uniquely long motor neurons evidence from cell culture studies and rare mutations in axonal transport genes, eg DCTN1
Oxidative stress	high energy requirements of motor neurons evidence from mutations in SOD1-based mouse models and cell culture
Neuroinflammation	microglial infiltrates seen post-mortem human MND and ­pre-symptomatic mouse models in vivo evidence from microglial PET of human MND brain
Mitochondrial dysfunction	abnormal mitochondria seen in post-mortem human MND association of SOD1 and TDP-43 altered neurophysiological properties in mouse and cell cultures
RNA biology	some genes linked to MND have key RNA processing roles, eg TARDBP, FUS, or have been associated with abnormal cellular RNA foci, eg C9orf72
Connectomics and prion-like spread	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
Nuclear-cytoplasmic transport	the cytoplasmic aggregation of TDP-43 that characterises nearly all cases of MND may be promoted by aberrant nuclear membrane transport

CSF = cerebrospinal fluid; FTD = frontotemporal dementia; MND = motor neuron disease; MRI = magnetic resonance imaging; PET = positron emission tomography