Copper and zinc containing superoxide dismutase (SOD1) plays a critical role in anti-oxidant defense, yet mutations in SOD1 can lead to amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, through a toxic gain of function. The underlying mechanism remains unclear, but an emerging theme involves SOD1 misfolding and formation of toxic SOD1 aggregates. A hypothesis of this research is that the fate of ALS mutant SOD1 is governed by intracellular factors that control post-translational modification of the polypeptide. We have identified a number of such factors, including the CCS copper chaperone, a CCS-independent pathway for activating SOD1, and cytosolic glutaredoxins that help reduce the SOD1 disulfide. Precisely how these factors impact on SOD1 in vivo will be addressed in two Aims of the current proposal:
Aim1 -To understand the pathways for activating human SOD1 with copper: A combination of genetics, biochemistry and structural analyses will explore how human SOD1 discerns between two pathways for acquiring copper and how CCS may uniquely promote SOD1 folding through proline isomerization.
Aim2 -To understand the impact of SOD1 interacting factors on the stability and aggregation of SOD1: Molecular genetic studies in yeast and tissue culture will dissect the opposing roles of the copper activation pathways versus the disulfide reduction pathways in the folding and aggregation of ALS mutant SOD1. ? ? In a separate but related line of research, this proposal will also address an unprecedented role for CCS in chromatin silencing:
Aim 3 -To understand the dual roles of CCS in SOD1 activation and chromatin silencing. Yeast genetics and biochemistry will address how CCS can promote both SOD1 activation and chromatin silencing through a possible mechanism involving the anti-aging factor SIR2. ? ? Together, these studies in both yeast and mammalian cells promise to shed new light into the biology of SOD1 and its metallochaperone CCS with important implications to disease. ? ?
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