Mutant Cu,Zn Superoxide Dismutase in Amyotrophic Lateral Sclerosis - Molecular Mechanisms of Neurotoxicity (Mutantti Cu,Zn-superoksididismutaasi amyotrofisessa lateraaliskleroosissa - Neurotoksisuuden molekulaariset mekanismit)
Year: 2008
Type: dissertation
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 charactherized by the selective destruction of upper and lower motor neurons in the spinal cord, brain stem and motor cortex.The majority of ALS cases are sporadic, whereas 5-10% of cases have a genetic component and are familial.The typical age of onset for both forms is between 50 and 60 years and prevalence is approximately 4-6 in 100 000 individuals per year.The causes for most cases of ALS are unknown and the clinical course is highly variable, suggesting that multiple factors underlie the disease mechanism.Mutations in the ubiquitously expressed protein, Cu,Zn-superoxide dismutase (SOD1), are associated with about 20% of familial ALS cases.Because the pathology and clinical symptoms of familial and sporadic ALS cannot be distinguished, transgenic animal models over-expressing mutant SOD1 offer a valuable tool for understanding the pathogenic mechanisms shared by both sporadic and familial forms of ALS.Importantly, several pathogenic SOD1 mutations do not affect SOD1 activity significantly, and a hypothesis for 'a toxic gain of function' of the mutated protein rather than a lack of its antioxidant function, has been postulated.In this work, we used transgenic ALS rats and mice to address the role of SOD1 in ALS pathogenesis by analyzing the proteomic profile in the spinal cord and by analyzing stability and oxidation state of human mutant SOD1 through the disease progression.In addition, we set out to investigate the role of mutant SOD1 in mitochondria.Results showed that mutant SOD1 is oxidized and destabilized in the affected tissues of the transgenic animals.A role of aggregation was further supported by the finding of increased chaperone expression in proteome profiling.Moreover, SOD1 may have a deleterious role in the intermembrane space of mitochondria, however, not because of aggregation, but caused instead by uncontrolled activity of the enzyme that can lead to increased production of harmful reactive oxygen species and damage to mitochondria.In addition, we also tested an anti-oxidant/inflammatory drug treatment with pyrrolidine dithiocarbamate for SOD1 transgenic ALS rats.However, the result of this drug treatment was unexpected as the treatment did not provide neuroprotection, but in opposite to the hypothesis, accelerated the disease progression.The mechanism of action showed a new target for the drug as the beneficial anti-oxidative and anti-inflammatory effects were overridden by a harmful inhibition of immunoproteasome induction.The results of this thesis show the importance of mammalian specific proteasome component in the disease pathogenesis of ALS.Moreover, our results demonstrate a new mitochondrial target and mechanism for SOD1 neurotoxicity that applies both to sporadic and familial ALS cases.
Author: Toni Ahtoniemi
Language: Finnish
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3096055395