Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg,C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

The dying forward hypothesis of motor neuron disease (MND) suggests that corticomotoneurons induce excitotoxic anterior horn cell death, with involvement of the glutamatergic neurotransmitter system. The aim of the present study was to apply novel threshold tracking transcranial magnetic stimulation (TMS) techniques in conjunction with peripheral nerve excitability studies in MND patients to further investigate the dying forward hypothesis and possibly determine the site of disease onset. Studies were undertaken in 23 MND patients using a 90-mm circular coil connected to a BiStim magnetic stimulator for cortical studies and electrical stimulation for peripheral nerve excitability studies. Motor-evoked potentials and compound muscle action potentials (CMAPs) were recorded from the right abductor pollicis brevis in the same setting. Measures of cortical and peripheral nerve excitability were correlated with clinical and neurophysiological parameters of disease severity. Short-interval intracortical inhibition (SICI) was significantly reduced in MND patients compared with controls (MND group = 3.6 ± 0.8%; controls = 8.5 ± 1.0%, P < 0.001), most prominently in MND patients with limb-onset disease. Changes in intracortical inhibition were accompanied by alterations in the magnetic stimulus–response curve, cortical silent period duration and resting motor threshold, all indicative of cortical hyperexcitability. Although the reduction in SICI was more pronounced in MND patients with less severe disease, as assessed by the CMAP amplitude, it remained evident even in MND patients with advanced disease. Measures of peripheral disease burden, namely the CMAP amplitude (r = −0.6) and neurophysiological index (r = −0.6), correlated with cortical hyperexcitability changes, as did the strength-duration time constant (r = −0.6), a peripheral marker of axonal excitability. Simultaneous assessment of central and peripheral nerve excitability has established the presence of co-existent upper and lower motor neuron dysfunction, with cortical hyperexcitability an early feature in MND.