ArticleNature communications2021
Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- Lessons in longevity from blood stem cells under protein stress.Trends in cell biology · 2026Review
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 2025Review
- A Disease-Associated Mutation Impedes PPIA through Allosteric Dynamics Modulation.Biochemistry · 2025Article
- A novel role for the peptidyl-prolyl cis-trans isomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex.EMBO reports · 2024Article
- Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing.Nature cell biology · 2024Article
- Interaction of theCells · 2023Article
- Metabolomics Approach Reveals Important Glioblastoma Plasma Biomarkers for Tumor Biology.International journal of molecular sciences · 2023Article
- Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins fromACS infectious diseases · 2023Article
- Article
- CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics.Neurotoxicity research · 2022Review
- Peptidyl Prolyl Isomerase A Modulates the Liquid-Liquid Phase Separation of Proline-Rich IDPs.Journal of the American Chemical Society · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.