Kieran, Dairin Mary; (2004) Preventing motoneuron degeneration in models of amyotrophic lateral sclerosis. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Selective motoneuron cell death is a defining pathological feature of Amyotrophic Lateral Sclerosis. Although the precise mechanism through which motoneurons die in this condition is unknown, numerous factors have been demonstrated to contribute to ALS pathogenesis. In this Thesis a number of strategies aimed at rescuing motoneurons from cell death are tested in both in-vitro and in-vivo models of motoneuron degeneration. The neuroprotective effect of compounds that manipulate a variety of endogenous cellular pathways, such as apoptotic and necrotic cell death pathways, as well as the heat shock response are examined. In the first part of this Thesis I examine the neuroprotective effect of inhibiting apoptotic and necrotic cell death pathways by treatment with caspase and calpain inhibitors. Using both primary cultures of ventral horn cells, as an in-vitro model of motoneuron degeneration, and an in-vivo nerve injury model of motoneuron degeneration, I examine whether inhibition of these cell death pathways can protect motoneurons from death. In the second part of this Thesis, experiments on mutant SOD1G93A mice, a well- established transgenic animal model of ALS are described. In these experiments I examine motoneuron degeneration in primary motoneuron cultures of mutant SOD mice to assess whether this is a suitable in-vitro model for studying disease pathogenesis. In addition the neuroprotective effect of enhancing an endogenous defence mechanism, the heat shock response, is examined in-vivo in mutant mice. In this study mutant SOD1G93A mice are treated with a specific co-inducer of heat shock proteins and I tested whether this novel treatment strategy had effects on disease progression and lifespan. Finally, the effect of inducing a mutation in cytoplasmic dynein in mutant SOD1G93A mice was explored. In these experiments Loa mice, with a mutation in dynein were crossbred with mutant SOD1G93A mice. Dyein is a cytoplasmic motor protein involved in axonal transport, and in Loa mice mutations in dynein have been reported to result in motoneuron degeneration (Hafezparast et al., 2003). This experiment was designed to examine the role of axonal transport in disease progression in mSOD1 mice, and to test whether a mutation in dynein would effect disease progresison in mSOD1 mice, such that disruption in axonal transport induced by a mutation in dynein is deleterious to these mice. The results in this Thesis show that motoneuron degeneration can be prevented by i) inhibition of cell death pathways after the activation of cell death, ii) by enabling endogenous cell defence mechanisms to help the cell help itself and prevent it from entering cell death pathways, iii) by establishing a unique crossbreeding programme of mutant/transgenic mice, where it was established that improving the axonal transport defects usually present in mSODl mice can significantly delay disease progression.

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