An Analysis of the Link Between Deubiquitinating Enzymes and ALS
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Our lab has investigated a model for the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) that involves aggregates of a mutant form of the protein SOD1 (mSOD1-G85R). We have identified proteins of interest that may be related to the process of mSOD1 aggregate formation through assays such as worm siRNA screens and microarray analysis. The primary focus of this thesis research is an experiment we conducted to corroborate a previous finding – namely that altering the expression of a specific deubiquitinating enzyme (DUB) has an impact on mSOD1-G85R aggregate formation – and thereby build support for a hypothesis we are developing regarding ALS pathogenesis. In addition to further investigating the relationship between this DUB and mSOD1-G85R, we conducted a microarray analysis that helped identify other proteins that may be related functionally to the DUB. In conjunction with a search of background literature, the microarray analysis uncovered several proteins of interest involved in tumor suppression pathways and copper homeostasis. A few models are proposed here for the possible link between these proteins of interest, the DUB we are investigating, and mSOD1-G85R aggregation with the goal of elucidating a pathogenetic mechanism underlying ALS. It can be concluded from the experimental results described in this thesis that further testing must be done to verify and subsequently better understand our proposed link between the expression of the DUB we identified and mSOD1 aggregation.