Characterisation of the heat shock response in a transgenic mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurodegenerative disorder characterised by the selective degeneration of motor neurones in the motor cortex, brainstem and spinal cord. There is no cure and no effective treatment for this disease. Approximately 20% of familial ALS cases are due to a mutation in the gene encoding Cu/Zn superoxide dismutase (SOD1). Heat shock proteins (Hsps) are intracellular chaperones that normally aid protein handling and prevent the aggregation and misfolding of proteins. Failure of the ubiquitin proteasome system (UPS) has been implicated in this disease leading to intracellular protein aggregation. It has previously been demonstrated that treatment of SOD1 mice with arimoclomol, a co-inducer of the heat shock response (HSR) has beneficial effects on disease progression. Much of the action of arimoclomol is not clear. In this study I examined possible alternative mechanisms of action of arimoclomol in SOD1 mice by investigating the effects of treatment on various markers of disease, including aggregation, inflammation, and ER stress. I also characterised components of the heat shock response (HSR) in disease progression of SOD1 mice and arimoclomol treated SOD1 mice. Western blot and immunohistochemical techniques were conducted. My results show that arimoclomol not only activates the heat shock response (HSR), causing increased expression of heat shock proteins (hsps) as well as important co- chaperones, but also considerably reduces aggregation, inflammation and ER stress. Arimoclomol could have therapeutic value for treatment of SOD1 mediated ALS in the future