Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators

Nat Struct Mol Biol. 2020 Feb;27(2):192-201. doi: 10.1038/s41594-020-0375-y. Epub 2020 Feb 10.


Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL), a rapidly progressing and lethal neurodegenerative disease with no treatment. ANCL mutations are proposed to trigger CSPα aggregation/oligomerization, but the mechanism of oligomer formation remains unclear. Here we use purified proteins, mouse primary neurons and patient-derived induced neurons to show that the normally palmitoylated cysteine string region of CSPα loses palmitoylation in ANCL mutants. This allows oligomerization of mutant CSPα via ectopic binding of iron-sulfur (Fe-S) clusters. The resulting oligomerization of mutant CSPα causes its mislocalization and consequent loss of its synaptic SNARE-chaperoning function. We then find that pharmacological iron chelation mitigates the oligomerization of mutant CSPα, accompanied by partial rescue of the downstream SNARE defects and the pathological hallmark of lipofuscin accumulation. Thus, the iron chelators deferiprone (L1) and deferoxamine (Dfx), which are already used to treat iron overload in humans, offer a new approach for treating ANCL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / metabolism
  • Humans
  • Iron Chelating Agents / metabolism
  • Lipoylation
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Neuronal Ceroid-Lipofuscinoses / genetics*
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Neurons / metabolism
  • Point Mutation*
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Binding
  • Protein Multimerization


  • HSP40 Heat-Shock Proteins
  • Iron Chelating Agents
  • Membrane Proteins
  • cysteine string protein