Pathology - Theses
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ItemThe mechanism of action of CuII(atsm) for the treatment of amyotrophic lateral sclerosis( 2015)Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the progressive loss of motor neurons in the spinal cord, motor cortex and brain stem leading to complete paralysis and death, usually within 2-3 years of diagnosis. There is currently no cure for ALS and the only approved therapeutic is riluzole. However, its clinical efficacy is marginal with an average extension in survival of 3 months. A subset of ALS cases (~10%) can be attributed to genetically inherited mutations in a number of different genes (familial ALS). Mutations in the gene for Cu,Zn superoxide dismutase (SOD1) – an antioxidant enzyme – were the first to be identified. These mutations lead to a toxic gain of function but the exact nature of this toxicity remains largely unknown. There is evidence to suggest that mutations may cause incorrect metallation of SOD1 leading to aberrant catalytic chemistry and misfolding. Over-expression of the mutant forms of the human protein in mice gives rise to a phenotype that recapitulates many of the symptoms of the human condition including progressive paralysis and premature death. The PET imaging agent, diacetyl-bis(4-methylthiosemicarbazonato)Cu(II) [CuII(atsm)] has been shown to have therapeutic potential in one of these models – SOD1G93A mice. In addition, CuII(atsm) has also been shown to be protective in multiple models of Parkinson's disease. The purpose of this thesis was to further characterise the therapeutic potential of CuII(atsm) in a second model of ALS and to determine if its therapeutic mechanism involves modulation of Cu bioavailability in disease affected tissue. CuII(atsm) was shown to have similar therapeutic potential in the SOD1G37R model as in the SOD1G93A model. Survival extension and improvement in locomotor symptoms were dependent on the dose administered with the highest dose administered proving to be the most effective. No apparent therapeutic ceiling was reached. CuII(atsm) was also co-administered with riluzole with no apparent additive or detrimental effects. When administered alone, riluzole was not as effective at attenuating symptoms and survival as CuII(atsm). Additionally, CuII(atsm) was therapeutic even when given post-onset of a locomotor deficit. Even though severity of disease symptoms in these mice is dependent on mutant SOD1 expression levels, treatment with CuII(atsm) was shown to paradoxically increase the concentration of mutant SOD1 in the spinal cord of these mice. This was due to an increase in fully metallated holo SOD1 – the stable, non-toxic form of the enzyme. The holo SOD1 pool was increased by incorporation of Cu from CuII(atsm) into the Cu-deficient, Zn-containing SOD1 pool. Several other proteins also incorporated Cu from CuII(atsm) however, not all detectable cuproproteins were targets of CuII(atsm)-mediated Cu delivery. Preliminary results suggest that the cuproprotein targets of CuII(atsm) are involved in oxidative stress, metal homeostasis and Cu delivery to SOD1, potentially inhibiting the toxic action of metal-deficient SOD1 on mitochondria. The clinical and pathological similarities between familial and sporadic ALS suggest that similar pathological processes occur in both forms of the disease. There is evidence to suggest that SOD1 can cause disease in the absence of mutations and there is ample evidence implicating mitochondrial dysfunction in sporadic ALS as well as familial ALS. CuII(atsm) is therefore a promising therapeutic for the treatment of ALS and the results presented and mechanism proposed in this thesis position CuII(atsm) as an excellent candidate for translation into human clinical trials.