Aggregation of Mutant Cysteine String Protein-α via Fe-S Cluster-Binding is mitigated by Fe-chelators

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), already in human use for treating iron-overload, offer a novel approach for treating ANCL.