Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators. Academic Article uri icon

Overview

abstract

  • 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 date

  • February 10, 2020

Research

keywords

  • HSP40 Heat-Shock Proteins
  • Membrane Proteins
  • Neuronal Ceroid-Lipofuscinoses
  • Point Mutation
  • Protein Aggregation, Pathological

Identity

PubMed Central ID

  • PMC7021000

Scopus Document Identifier

  • 85079232326

Digital Object Identifier (DOI)

  • 10.1038/s41594-020-0375-y

PubMed ID

  • 32042150

Additional Document Info

volume

  • 27

issue

  • 2