Cellular and molecular mechanisms of motor neuron vulnerability in degenerative disease and injury
Kline, Rachel Ann
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The distal compartments of the motor neuron represent early and significant targets across situations of both neurodegenerative disease and traumatic injury. In this thesis, we address two distinct scenarios of axonal and synaptic degeneration. First, we explore neuromuscular junction pathology in a mouse model of the heritable motor neuron disease spinal muscular atrophy (SMA) and address the capacity for neuronal regeneration following restoration of the pathologically depleted Survival Motor Neuron (SMN) protein. We demonstrate that motor neurons exhibit a robust and phenotypically translatable recovery from considerable levels of cellular and molecular dysfunction. In the second chapter, we explore the phenomenon of delayed Wallerian degeneration in neonatal mice. We employ a quantitative mass spectrometry approach to profile proteins exhibiting a temporal expression pattern in line with previously observed postnatal changes in axonal and synaptic vulnerability to injury. We then utilise a variety of proteomics tools to identify pathways which may mechanistically contribute to age-dependent resistance to degeneration. Together, these results provide a preliminary insight into the cellular and molecular mechanisms underlying motor neuron vulnerability in two independent models of degenerative disease and injury.