This thesis examines the pathophysiology of motor neurone dysfunction, along with site of disease onset, in amyotrophic lateral sclerosis (ALS). The rationale for this thesis is the "dying forward" hypothesis, which suggests that corticomotoneurons cause anterograde excitotoxic degeneration of motor neurons in ALS. Initially, axonal excitability studies were applied to ALS patients and revealed widespread axonal ion channel dysfunction, with increases in persistent Na+ conductances and reduction in K+ currents. Such changes result in axonal hyperexcitability, thereby resulting in generation of fasciculations and cramps. Subsequently, axonal excitability studies were applied to Kennedy's disease (KD) patients, a pathological control group, revealing similar changes to ALS and suggesting that upregulation of persistent Na+ conductances was responsible for generation of fasciculations. To better understand the mechanisms underlying fatigability and to assess whether Na+/K+ pump dysfunction contributes to neurodegeneration in ALS, activity-dependent changes in axonal excitability were measured after a maximal voluntary contraction. The increase in threshold was more pronounced in ALS patients with predominantly lower motor neuron involvement, suggesting that peripheral factors were responsible for fatigue in ALS and that Na+/K+ pump function was preserved. Having documented abnormalities of axonal excitability, a novel threshold tracking transcranial magnetic stimulation (TMS) technique was developed for assessment of cortical excitability. This technique overcomes the marked variability in the motor evoked potential with consecutive stimuli, a major limitation of the previous "constant stimulus" technique. After establishing normative data, threshold tracking TMS established that cortical hyperexcitability was an early and prominent feature in ALS. Similar changes were found in flail-arm variant ALS, a pure lower motor neuron form of ALS. In KD patients, cortical excitability was normal, thereby suggesting that cortical hyperexcitability is a primary event in ALS rather than a down-regulation of inhibitory control over the motor cortex in order to compensate for anterior horn cell loss. In order to determine whether cortical hyperexcitability underlies motor neurodegeneration, longitudinal studies were undertaken in familial ALS subjects with the copper/zinc superoxide-dismutase-1 gene mutation. These studies established that cortical hyperexcitability precedes the development of clinical ALS, thereby suggesting that cortical hyperexcitability underlies the basis of motor neurodegeneration in familial ALS.

This thesis examines the pathophysiology of motor neurone dysfunction, along with site of disease onset, in amyotrophic lateral sclerosis (ALS). The rationale for this thesis is the "dying forward" hypothesis, which suggests that corticomotoneurons cause anterograde excitotoxic degeneration of motor neurons in ALS. Initially, axonal excitability studies were applied to ALS patients and revealed widespread axonal ion channel dysfunction, with increases in persistent Na+ conductances and reduction in K+ currents. Such changes result in axonal hyperexcitability, thereby resulting in generation of fasciculations and cramps. Subsequently, axonal excitability studies were applied to Kennedy's disease (KD) patients, a pathological control group, revealing similar changes to ALS and suggesting that upregulation of persistent Na+ conductances was responsible for generation of fasciculations. To better understand the mechanisms underlying fatigability and to assess whether Na+/K+ pump dysfunction contributes to neurodegeneration in ALS, activity-dependent changes in axonal excitability were measured after a maximal voluntary contraction. The increase in threshold was more pronounced in ALS patients with predominantly lower motor neuron involvement, suggesting that peripheral factors were responsible for fatigue in ALS and that Na+/K+ pump function was preserved. Having documented abnormalities of axonal excitability, a novel threshold tracking transcranial magnetic stimulation (TMS) technique was developed for assessment of cortical excitability. This technique overcomes the marked variability in the motor evoked potential with consecutive stimuli, a major limitation of the previous "constant stimulus" technique. After establishing normative data, threshold tracking TMS established that cortical hyperexcitability was an early and prominent feature in ALS. Similar changes were found in flail-arm variant ALS, a pure lower motor neuron form of ALS. In KD patients, cortical excitability was normal, thereby suggesting that cortical hyperexcitability is a primary event in ALS rather than a down-regulation of inhibitory control over the motor cortex in order to compensate for anterior horn cell loss. In order to determine whether cortical hyperexcitability underlies motor neurodegeneration, longitudinal studies were undertaken in familial ALS subjects with the copper/zinc superoxide-dismutase-1 gene mutation. These studies established that cortical hyperexcitability precedes the development of clinical ALS, thereby suggesting that cortical hyperexcitability underlies the basis of motor neurodegeneration in familial ALS.

Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1- controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3- restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and nonmalignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.