ArticleProtein science : a publication of the Protein Society2021
Frontotemporal dementia-linked P112H mutation of TDP-43 induces protein structural change and impairs its RNA binding function.
Article in Protein science : a publication of the Protein Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 38 citations in OpenAlex.
- Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.Science (New York, N.Y.) · 2026Article
- Topological machine learning for protein-nucleic acid binding affinity changes upon mutation.Machine learning: science and technology · 2025Article
- TRAF6 regulates ubiquitination-independent TDP-43 condensation and related neurodegeneration.Molecular psychiatry · 2025Article
- Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.bioRxiv : the preprint server for biology · 2025Article
- Elevated nuclear TDP-43 induces constitutive exon skipping.Molecular neurodegeneration · 2024Article
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
- RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.eLife · 2023Article
- Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions.Frontiers in neuroscience · 2022Review
- Mechanisms of TDP-43 Proteinopathy Onset and Propagation.International journal of molecular sciences · 2021Review
- Frontotemporal dementia-linked P112H mutation of TDP-43 induces protein structural change and impairs its RNA binding function.Protein science : a publication of the Protein Society · 2021Article
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4 authors at 1 institution in 1 country.
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Abstract
TDP-43 forms the primary constituents of the cytoplasmic inclusions contributing to various neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Over 60 TDP-43 mutations have been identified in patients suffering from these two diseases, but most variations are located in the protein's disordered C-terminal glycine-rich region. P112H mutation of TDP-43 has been uniquely linked to FTD, and is located in the first RNA recognition motif (RRM1). This mutation is thought to be pathogenic, but its impact on TDP-43 at the protein level remains unclear. Here, we compare the biochemical and biophysical properties of TDP-43 truncated proteins with or without P112H mutation. We show that P112H-mutated TDP-43 proteins exhibit higher thermal stability, impaired RNA-binding activity, and a reduced tendency to aggregate relative to wild-type proteins. Near-UV CD, 2D-nuclear-magnetic resonance, and intrinsic fluorescence spectrometry further reveal that the P112H mutation in RRM1 generates local conformational changes surrounding the mutational site that disrupt the stacking interactions of the W113 side chain with nucleic acids. Together, these results support the notion that P112H mutation of TDP-43 contributes to FTD through functional impairment of RNA metabolism and/or structural changes that curtail protein clearance.
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