Mechanisms of cortical and respiratory degenerations in Amyotrophic Lateral Sclerosis (2016–2021)
In Australia, 2 adult deaths each day and ~1900 people are living with significant disability due to Amyotrophic Lateral Sclerosis, or ALS (Aust. Bureau of Statistics, 2009). ALS is a progressive neurodegenerative disorder clinically characterized by loss of upper motor neurons (MNs) of the motor cortex and corticospinal tract (including layer V pyramidal neurons (LVPNs)) and lower MNs of the brainstem and spinal cord. Clinically, lower MNs that receive no cortical inputs are spared. Furthermore, cortical hyper-excitation, a key determinant in clinical progression, may occur prior to clinical symptoms and separates ALS from other neuro-motor disorders. While spinal cord MN loss and subsequent locomotor deficiencies cause the initial symptoms of muscle weakness, cause of death in ALS is paralysis of respiratory muscles. Respiratory muscle function is also the best correlative measure of disease progression and quality of life for ALS sufferers. Although both cortical and spinal degeneration is pathognomic for ALS, very little is known about the timing of the molecular mechanisms (common and disparate) underpinning degenerations of the upper and lower MN axis in ALS. This study uses the SOD1G93A (SOD1) and TDP-43 mouse models of ALS to assess neuro-degeneration at the molecular, cellular, circuit and neuro-motor system levels. The key focus of this project will be to describe the sub-cellular mechanics and functional alterations of motor cortical LVPNs and phrenic respiratory MN degeneration in ALS, in relation to the proposed disease mechanism, glutamategic excito-toxicity. Ex vivo (brain slice) cortical LVPNs and spinal phrenic MNs will be assessed for irregularities in cell calcium, mitochondrial homeostasis and differences in expression levels of ion channel synaptic components. This project will unearth new therapeutic targets and critical time-points for intervention for this incurable disease.