Yip, J; (2012) Harnessing the heat shock response as a therapeutic approach in models of MND. Doctoral thesis , UCL (University College London).

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that leads to muscle atrophy, paralysis of voluntary muscles and death. ALS is characterized by the selective degeneration of upper and lower motoneurons in the spinal cord, brain stem and motor cortex. The maJority of ALS cases are sporadic, whereas 10 - 20Z of cases have a genetic component and are familial. The causes for most cases of ALS are unknown and the clinical course is highly variable, suggesting that multiple factors underlie the disease mechanism. Recent experimental evidence has illustrated that selective motoneurons degeneration in ALS does not arise solely within motoneurons. The involvement of non-neuronal cells, such as astrocytes, in the pathogenesis of ALS have recently been shown with convincing data supporting the hypothesis of non-cell autonomous mechanism in which motoneuron degenerations is influenced by the toxicity of non-neuronal cells surrounding the motoneurons. In view of this crucial interaction between astrocytes and motoneurons and the implication of astrocytes in ALS disease progression, the role of astrocytes will be examined. An in vitro approach is employed in order to examine the role of mutant SOD1 protein expression in primary astrocyte cells. Motoneurons have an unusually high threshold for induction of heat shock proteins (Hsps), which may contribute to their susceptibility in ALS compared to astrocytes. Thus by increasing the heat shock response (HSR), the cytoprotective mechanism in astrocytes, as a result of up-regulation of Hsp expression within these cells, is a potential therapeutic target. This neuroprotective effect of manipulating the HSR system is investigated in vitro in SOD1G93A transgenic mice. Furthermore, characterization of astrocytes was also carried out in vivo of the cortex and spinal cord in SOD1G93A transgenic mice. Finally, the effect of co- inducing the HSR system in astrocytes by pharmacological manipulation is assessed. The data of the present study clearly indicate that expression of mutant SOD1 protein in astrocytes causes a stress response, and successful manipulation of the increased HSR system in primary astrocytes causes an increase in primary motoneurons survival. Thus targeting the HSR in astrocytes in proximity of motoneurons may be a successful therapeutic approach by circumventing motoneuron degenerations in ALS.

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