ArticleThe EMBO journal2022
C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation.
Article in The EMBO journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- FRET-based biosensor moxCRONOS enables quantitative monitoring of macromolecular crowding in organelles and protein aggregates.Journal of biochemistry · 2025Article
- Allosteric modulation of protein kinase A in individuals affected by NLPD-PKA, a neurodegenerative disease in which the PRKAR1B L50R variant is expressed.The FEBS journal · 2025Article
- Therapeutic Approaches for C9ORF72-Related ALS: Current Strategies and Future Horizons.International journal of molecular sciences · 2025Review
- Targeting GeneInternational journal of molecular sciences · 2025Review
- RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.Life science alliance · 2025Article
- Mineralocorticoid Receptor Antagonists and Cognitive Outcomes in Cardiovascular Disease and Beyond: A Systematic Review.Journal of personalized medicine · 2025Review
- Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.Nature communications · 2025Article
- Decoding Nucleotide Repeat Expansion Diseases: Novel Insights fromInternational journal of molecular sciences · 2024Review
- Mapping of repeat-associated non-AUG (RAN) translation knowledge: A bibliometric analysis.Heliyon · 2024Article
- Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.Science advances · 2024Article
- Flight to insight: maximizing the potential ofFrontiers in molecular neuroscience · 2024Article
- Current potential therapeutics of amyotrophic lateral sclerosis.Frontiers in neurology · 2024Review
- Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD.Nature communications · 2023Article
- Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.Cells · 2023Review
- Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS/FTDCurrent research in neurobiology · 2023Article
- Review
- Multiple roles for the cytoskeleton in ALS.Experimental neurology · 2022Review
- Gene Therapy in Amyotrophic Lateral Sclerosis.Cells · 2022Review
- The polyG diseases: a new disease entity.Acta neuropathologica communications · 2022Review
- C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation.The EMBO journal · 2022Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 3 countries.
Funding
Abstract
Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD.
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Registered trials
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.