ArticleProceedings of the National Academy of Sciences of the United States of America2021
ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 40 citations in OpenAlex.
- F-Box and Leucine-Rich Repeat Protein 4 (FBXL4) Maintains Sarcomere Integrity and Cardiac Function by Enhancing K48-Linked Ubiquitinated Degradation of Profilin-1 (PFN1).Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- RAGE Axis in the Pathogenesis and Treatment of CNS Neurodegeneration in Long-Term Hyperglycemia.International journal of molecular sciences · 2026Review
- Profilin and Non-Canonical Wnt Signaling: Coordinating Cytoskeletal Dynamics from Development to Disease.Journal of developmental biology · 2025Review
- Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.Pathophysiology : the official journal of the International Society for Pathophysiology · 2025Review
- Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1Acta neuropathologica communications · 2025Article
- Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson's disease.Acta neuropathologica communications · 2025Article
- Neural Excitatory/Inhibitory Imbalance in Motor Aging: From Genetic Mechanisms to Therapeutic Challenges.Biology · 2025Review
- Using ALS to understand profilin 1's diverse roles in cellular physiology.Cytoskeleton (Hoboken, N.J.) · 2025Review
- Quantitative Proteomics Identifies Profilin-1 as a Pseudouridine-Binding Protein.Journal of the American Chemical Society · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Prolonged depletion of profilin 1 or F-actin causes an adaptive response in microtubules.The Journal of cell biology · 2024Article
- The physical and evolutionary energy landscapes of devolved protein sequences corresponding to pseudogenes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.Nature communications · 2024Article
- Proximity Proteomics Revealed Aberrant mRNA Splicing Elicited by ALS-Linked Profilin-1 Mutants.Analytical chemistry · 2023Article
- Nuclear Actin Polymerization Regulates Cell Epithelial-Mesenchymal Transition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.FEBS letters · 2023Review
- Vascular endothelial cell-specific disruption of thePNAS nexus · 2023Article
- Cytoskeletal adaptation following long-term dysregulation of actomyosin in neuronal processes.bioRxiv : the preprint server for biology · 2023Article
- Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Profilin-1 (PFN1) plays important roles in modulating actin dynamics through binding both monomeric actin and proteins enriched with polyproline motifs. Mutations in PFN1 have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, whether ALS-linked mutations affect PFN1 function has remained unclear. To address this question, we employed an unbiased proteomics analysis in mammalian cells to identify proteins that differentially interact with mutant and wild-type (WT) PFN1. These studies uncovered differential binding between two ALS-linked PFN1 variants, G118V and M114T, and select formin proteins. Furthermore, both variants augmented formin-mediated actin assembly relative to PFN1 WT. Molecular dynamics simulations revealed mutation-induced changes in the internal dynamic couplings within an alpha helix of PFN1 that directly contacts both actin and polyproline, as well as structural fluctuations within the actin- and polyproline-binding regions of PFN1. These data indicate that ALS-PFN1 variants have the potential for heightened flexibility in the context of the ternary actin-PFN1-polyproline complex during actin assembly. Conversely, PFN1 C71G was more severely destabilized than the other PFN1 variants, resulting in reduced protein expression in both transfected and ALS patient lymphoblast cell lines. Moreover, this variant exhibited loss-of-function phenotypes in the context of actin assembly. Perturbations in actin dynamics and assembly can therefore result from ALS-linked mutations in PFN1. However, ALS-PFN1 variants may dysregulate actin polymerization through different mechanisms that depend upon the solubility and stability of the mutant protein.
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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.