Dimer stabilization and aggregation of superoxide dismutase
Subtitle: by Andrew Patrick Choi
Published: 2008
Language: eng
Number of pages: 135
Description: Within a subset of familial Amyotrophic Lateral Sclerosis (FALS), over one hundred different mutations in the Cu/Zn superoxide dismutase gene (SOD1) are linked to the disease. Though SOD1 functions as an important free radical scavenger, the mechanism of toxicity in SOD1-associated FALS has been clearly shown to be a gain of function. In FALS, as in many other neurodegenerative diseases, aberrant aggregation is thought to play a major role in disease etiology. The work in this thesis was undertaken to investigate the role of dimer stabilization in preventing SOD1 aggregation, as well as potential mechanisms of toxicity when stabilization fails and aggregation occurs. Chapter 1 presents an overview of SOD1 and its involvement in FALS, as well as prevalent hypotheses of toxicity. In Chapter 2, a novel fluorescence-based assay of SOD1 WT and mutant dimer dissociation is described that is amenable to high- throughput screening for potentially therapeutic compounds. The assay has several variant readouts, all of which have been validated with known SOD1 aggregation-inhibiting compounds. We have also used the assay as a tool for investigating the relative stabilities of SOD1 heterodimers, as shown in Chapter 3. Given the native dimeric state of SOD1, heterodimer kinetics has previously been problematic to study. Finally, in Chapter 4, we demonstrate the specific release of cytochrome c from purified mouse mitochondria by aggregated oligomeric SOD1, and hypothesize as to mechanisms of toxicity. Altogether, this work illustrates the impact of SOD1 dimer stabilization on aggregation, and highlights a possible consequence of failing to prevent aggregation.
Notes: "April 2008."

Thesis (Ph.D., Division of Medical Sciences (Biological Chemistry and Molecular Pharmacology)--Harvard University, 2008.

Includes bibliographical references.