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An intramolecular salt bridge linking TDP43’s RNA recognition motifs dictates RNA binding, protein stability and TDP43-dependent neurodegeneration

ABSTRACT: The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relationship between TDP43’s RNA binding properties and neurodegeneration remain obscure. Here we show that engineered mutations disrupting a salt bridge between TDP43’s RNA recognition motifs interfere with nucleic acid binding and eliminate recognition of native TDP43 substrates. The accumulation of WT TDP43, but not RNA binding-deficient variants, disproportionately affected the abundance and splicing of encoding ribosome and oxidative phosphorylation components.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128647 | GEO | 2019/03/22

REPOSITORIES: GEO

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An intramolecular salt bridge linking TDP43’s RNA recognition motifs dictates RNA binding, protein stability and TDP43-dependent neurodegeneration

Project description:An intramolecular salt bridge linking TDP43’s RNA recognition motifs dictates RNA binding, protein stability and TDP43-dependent neurodegeneration

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TDP43 proteinopathy exhibits disease, tissue, and context-specific cryptic splicing signatures

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2024-03-28 | GSE255683 | GEO

An Intramolecular Salt Bridge Linking TDP43 RNA Binding, Protein Stability, and TDP43-Dependent Neurodegeneration.

Project description:The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relation between the RNA binding properties of TDP43 and neurodegeneration remains obscure. Here, we show that engineered mutations disrupting a salt bridge between the RNA recognition motifs of TDP43 interfere with RNA binding and eliminate the recognition of native TDP43 substrates. The same mutations dramatically destabilize TDP43, alter its subcellular localization, and abrogate TDP43-dependent neurodegeneration. Worms harboring homologous TDP-1 mutations phenocopy knockout strains, confirming the necessity of salt bridge residues for TDP43 function. Moreover, the accumulation of functional TDP43, but not RNA binding-deficient variants, disproportionately affects transcripts encoding ribosome and oxidative phosphorylation components. These studies demonstrate the significance of the salt bridge in sustaining TDP43 stability and RNA binding properties, factors that are crucial for neurodegeneration arising from TDP43 deposition in ALS and FTD.

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Stress granules protect ER-exit sites from TDP43 aggregation

Project description:Aggregation of proteins under cellular stress plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and physiological consequences is poorly understood. We employed a general reporter to identify proteins forming aggregates under proteotoxic stress in human cells. Over 300 proteins were identified, forming different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule (SG) and a previously unknown solid inclusion containing components of the ER exit sites (ERES), such as SEC16A. TDP43 accumulation at ERES is antagonized by SG assembly, but enhanced by certain ALS-associated mutations. TDP43-ERES aggregation biases toward nascent TDP43 and, unlike SG, does not contain RNA. Such aggregation causes defects in ER-to-Golgi protein transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patient neurons.

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Project description:TDP43 is involved in microRNA biogenesis and found in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS), and microRNAs are important for regulation of gene expression and represent potential biomarkers and therapeutic targets. Therefore, we examined microRNAs that preferentially bind cytoplasmic TDP43 using cellular models expressing TDP43 variants and NanoString miRNA profiling analyses. We identified cytoplasmic TDP43-associated miRNAs and predicted genes and pathways to gain insights into potentially relevant disease pathways, biomarkers, and reversible therapeutic targets for ALS.

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PCBP1/2 and TDP43 Function As NAT10 Adaptors In ac4C Writer Complex Towards mRNAs in Mammalian Cells [293T_acRIPseq]

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2024-08-23 | GSE248404 | GEO

Individual-nucleotide resolution CLIP and high-throughput sequencing for FOX2, TDP43 and hnRNP M in WT and P-KO H9 cells

Project description:Individual-nucleotide resolution UV-crosslinking and immunoprecipitation (iCLIP) combined with high-throughput sequencing was used to generate a transcriptome-wide binding map of TDP43, FOX2 and hnRNP M in WT and P-KO H9 cells.

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