Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel

Sara S. Ribeiro, David Gnutt, Salome Azoulay-Ginsburg, Zamira Fetahaj, Ella Spurlock, Felix Lindner, Damon Kuz, Yfat Cohen-Erez, Hanna Rapaport, Adrian Israelson, Arie Lev Gruzman, Simon Ebbinghaus

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.

Original languageEnglish
Pages (from-to)909-930
Number of pages22
JournalBiological Chemistry
Volume404
Issue number10
DOIs
StatePublished - 26 Sep 2023

Bibliographical note

Publisher Copyright:
© 2023 the author(s), published by De Gruyter, Berlin/Boston.

Keywords

  • SOD1
  • chemical chaperones
  • organelle-targeting therapy
  • osmolytes
  • protein folding and aggregation
  • targeted drugs

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