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Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder, characterised by the loss of motoneurons in the motor cortex, brainstem and spinal cord, leading to muscle atrophy and eventual paralysis. Despite intensive research the mechanisms that underlie the selective vulnerability of motoneurons in ALS remain unclear. Recent results have shown the involvement of non-neuronal cells in the central nervous system, such as glia in the pathogenesis of ALS. However the role of other cells in the peripheral nervous system, which also functionally interact with motoneurons, such as skeletal muscle, has not yet been established. In this thesis the role of skeletal muscle in ALS pathogenesis was investigated. Transgenic SODlG93A mice are a commonly used model of ALS, which closely resemble several features of human ALS. In this Thesis, experiments were performed to examine the effect of mutant SOD1 expression in muscles and examined the effect of motoneurons on the cellular properties of muscles, using an in vitro co-culture system. The results presented in Chapter 3 show that mitochondrial dysfunction and aberrant calcium signalling arises in mutant SOD 1 motoneurons and is influenced by muscles at an early stage in development. Furthermore the loss of target derived neurotrophic support has been implicated in ALS and promising effects have been obtained from IGF-I in SODlG93A mice. The potential neuroprotective effect of MGF, a splice variant of IGF-I was investigated in vivo in SODlG93A mice. The results presented in Chapter 4 show that MGF has potent neuroprotective effect in SOD 1093A mice. Both IGF-I and MGF were effective in improving muscle strength, increasing motor unit survival and delaying the progression of the disease. However the muscle restricted expression of MGF significantly improved motoneuron survival to a greater extent that IGF-I in SODlG93A mice. The results of this research highlight skeletal muscle as an appropriate target to deliver therapeutic strategies to prevent motoneuron degeneration in ALS and suggest that early deficits, in muscle in particular, in mitochondrial function may play a role in ALS pathogenesis. |
