ArticleNature structural & molecular biology2020
Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators.
Article in Nature structural & molecular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- Article
- CHIP protects lysosomes from CLN4 mutant-induced membrane damage.Nature cell biology · 2025Article
- Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency.Science advances · 2025Article
- Cysteine string protein α and a link between rare and common neurodegenerative dementias.NPJ dementia · 2025Review
- Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons.Science advances · 2024Article
- Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome.The Biochemical journal · 2024Article
- Review
- Unveiling the Molecular Footprint: Proteome-Based Biomarkers for Alzheimer's Disease.Proteomes · 2023Review
- A Caenorhabditis elegans model of autosomal dominant adult-onset neuronal ceroid lipofuscinosis identifies ethosuximide as a potential therapeutic.Human molecular genetics · 2023Article
- Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPα mutants causes lipofuscin accumulation.Autophagy · 2023Article
- Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models.Nature communications · 2022Article
- Adult-Onset Neuronal Ceroid Lipofuscinosis With a NovelFrontiers in aging neuroscience · 2022Article
- Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy.Frontiers in cell and developmental biology · 2022Review
- Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer's disease.Brain communications · 2022Article
- CSPα in neurodegenerative diseases.Frontiers in aging neuroscience · 2022Review
- Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis.Clinical genetics · 2021Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
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.
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