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Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1
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Neurodegenerative diseases share a common characteristic, the presence of intracellular or extracellular deposits of protein aggregates in nervous tissues. Amyotrophic Lateral Sclerosis (ALS) is a severe and fatal neurodegenerative disorder, which affects preferentially motoneurons. Changes in the redox state of superoxide dismutase 1 (SOD1) are associated with the onset and development of familial forms of ALS. In human SOD1 (hSOD1), a conserved disulfide bond and two free cysteine residues can engage in anomalous thiol/disulfide exchange resulting in non-native disulfides, a hallmark of ALS that is related to protein misfolding and aggregation. Because of the many competing reaction pathways, traditional bulk techniques fall short at quantifying individual thiol/disulfide exchange reactions. Here, we adapt recently developed single-bond chemistry techniques to study individual disulfide isomerization reactions in hSOD1. Mechanical unfolding of hSOD1 leads to the formation of a polypeptide loop held by the disulfide. This loop behaves as a molecular jump rope that brings reactive Cys-111 close to the disulfide. Using force-clamp spectroscopy, we monitor nucleophilic attack of Cys-111 at either sulfur of the disulfide and determine the selectivity of the reaction. Disease-causing mutations G93A and A4V show greatly altered reactivity patterns, which may contribute to the progression of familial ALS.
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SOLSONA SANCHO, Carles, KAHN, Thomas b., BADILLA, Carmen l., ÁLVAREZ ZALDIERNAS, Cristina, BLASI CABÚS, Joan, FERNÁNDEZ, Julio m., ALEGRE-CEBOLLADA, Jorge. Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1. _Journal of Biological Chemistry_. 2014. Vol. 289, núm. 39, pàgs. 26722-26732. [consulta: 1 de febrer de 2026]. ISSN: 0021-9258. [Disponible a: https://hdl.handle.net/2445/176729]