Protein crosslinking as a therapeutic strategy for SOD1-related ALS

Abstract

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS). One effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers. Considerable research efforts have been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but these have not yet resulted in an approved drug. We demonstrate that a cyclic thiosulfinate cross-linker can stabilize prevalent disease-causing SOD1 variants. The degree of stabilization afforded by cyclic thiosulfinates (up to 24 degC) is unprecedented. We show this compound works rapidly in vivo with a half-life of ~3 days. The efficacy, low toxicity, and pharmacodynamics of cross-linker mediated stabilization make it a promising therapeutic approach for SOD1-related fALS.

Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

“…We expect that some degree of anti-SOD1 nanobody target engagement with SOD1 WT will not preclude their therapeutic utility, as ectopic Nb61 expression was not toxic to human neurons expressing SOD1 WT or mutant SOD1 A4V. Furthermore, enhancement of SOD1 WT levels may be preferred and possibly beneficial over a reduction in SOD1, particularly in a disease context for which there is elevated oxidative stress [3,5,15,24,58,59]. Additionally, a beneficial effect has been observed in ALS-SOD1 models upon treatment with diacetylbis(4-methylthiosemicarbazonato) copper(II) (Cu(II)(atsm)), which promotes metalation and increases the levels of SOD1 [60][61][62].…”

Oxidation of Dueling Cysteine Promotes Subunit Exchange in SOD1

“…Cysteine-111 is solvent exposed (Figure 1), reactive, and a therapeutic target in SOD1-linked ALS. 40,41 Cysteine-111 can undergo selective oxidation to form sulfenic (R-SOH), sulfinic (R-SO 2 − ), and sulfonic (R-SO 3 − ) acids. 34,42−44 In general, the oxidation of cysteine plays a functional role in redox signaling.…”

“…The SOD1 monomer contains two free cysteines: C6 and C111. Cysteine-111 is solvent exposed (Figure ), reactive, and a therapeutic target in SOD1-linked ALS. , Cysteine-111 can undergo selective oxidation to form sulfenic (R-SOH), sulfinic (R-SO 2 – ), and sulfonic (R-SO 3 – ) acids. ,− In general, the oxidation of cysteine plays a functional role in redox signaling. − The SOD1 enzyme is predisposed to cysteine oxidation, per se , as both reactants and products of SOD1 catalysis (O 2 •– , O 2 , and H 2 O 2 ) can oxidize cysteine. , Cysteine-111 oxidation in SOD1 has been hypothesized to play a role in ALS by accelerating certain types of SOD1 aggregation or altering proteostasis. ,,, Regardless of the role of oxidative stress in SOD1-linked ALS, we are interested (in this paper) in simply determining how C111 oxidation affects the rate and Δ G Het of WT/mutant heterodimerization.…”