GSE121569
GSE GEO Potentially relatedALS implicated protein TDP-43 sustains levels of STMN2 a mediator of motor neuron growth and repair
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Summary
The discovery that TDP-43 mutations cause familial ALS and that many patients display pathological TDP-43 mislocalization has nominated altered RNA metabolism as a potential disease mechanism. Despite its importance, the identity of RNAs regulated by TDP-43 in motor neurons remains poorly understood. Here, we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, we found STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown, in patient-specific motor neurons, following TDP-43 mislocalization, and in the postmortem patient spinal cords. Loss of STMN2 upon reduced TDP-43 function was due to the emergence of a cryptic exon, which is of substantial functional importance, as we further demonstrate that STMN2 is necessary for both axonal outgrowth and repair. Importantly, post-translational stabilization of STMN2 could rescue neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose restoring STMN2 expression warrants future examination as an ALS therapeutic strategy.
Overall Design
Transcriptome differential expression analysis in HUES3 cells with and without siRNA knockdown of TDP-43
Analysis (12 steps)
View Data Processing- All FASTQ files were analyzed using the bcbioRNASeq workflow and toolchain91.
- The FASTQ files were aligned to the GRCh37/hg19 reference genome.
- Differential expression testing was performed using DESeq2 suite of bioinformatics tools38.
- The DEXSeq module of Bioconductor was used to identify differential splicing92.
- We used salmon to generate the counts and tximport to load them at gene level93,94.
- All p-values are then corrected for multiple comparisons using the method of Benjamini and Hochberg95.
- We used an adjusted p-value cutoff of 0.05 with no log fold-change ratio cutoff for differential gene expression analysis and a 0.1 cutoff with no log fold-change ratio cutoff for differential exon usage.
- [tpm.csv.gz] gene x sample matrix of TPM for each sample
Supplementary Files (5)
Dataset Citations (1)
Potentially Related Publications (1)
This accession was text-mined from the PMC full text of these publications. It may be referenced for comparison or reused from another study rather than generated for them.
Data Files (10)
| Accession | File Name | Stored Type | Output Type | Mapping Assembly | Size | Download | |
|---|---|---|---|---|---|---|---|
| — | BD_22_1.fastq.gz | RNA-Seq | 2.3 GB | link | |||
| — | BD_23_1.fastq.gz | RNA-Seq | 1.6 GB | link | |||
| — | BD_24_1.fastq.gz | RNA-Seq | 1.9 GB | link | |||
| — | BD_25_1.fastq.gz | RNA-Seq | 1.7 GB | link | |||
| — | BD_30_1.fastq.gz | RNA-Seq | 1.1 GB | link | |||
| — | BD_31_1.fastq.gz | RNA-Seq | 1.3 GB | link | |||
| — | BD_32_1.fastq.gz | RNA-Seq | 1.4 GB | link | |||
| — | BD_33_1.fastq.gz | RNA-Seq | 1.2 GB | link | |||
| — | BD_34_1.fastq.gz | RNA-Seq | 1.2 GB | link | |||
| — | BD_35_1.fastq.gz | RNA-Seq | 1.2 GB | link |