Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Comprehensive Transcriptomic Analysis of NSC34 Motor Neurons following TDP43 Modulation: Knockdown vs. Control and Wild Type vs. TDP43 M337V Mutation

ABSTRACT: Transactive response DNA binding protein of 43 kDa (TDP43) is a ribonucleoprotein integral to several neurodegenerative diseases. Under normal conditions, TDP43 primarily localizes in the nucleus, where it plays a crucial role in RNA metabolism. Its function necessitates shuttling between the nucleus and cytoplasm. TDP43 dysfunction plays a significant role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and Parkinson’s disease. A common dysfunction of TDP43 is nuclear depletion and cytoplasmic aggregation of the protein. Additionally, aggregation-prone mutations, such as the TDP43M337V mutation, exacerbate TDP43 mislocalization to the cytoplasm, increasing neuronal toxicity. Given TDP43's critical role in RNA processing, its depletion or mutation disrupts the transcriptomic landscape, leading to aberrant RNA processing and splicing. In this study, we employed a library preparation method capturing both coding and noncoding RNA, generating a comprehensive nuclear transcriptomic dataset following TDP43 knockdown or mutant TDP43M337V expression in NSC34 motor neurons. This nuanced strategy significantly enhances our understanding of the intricate interplay between TDP43 dysfunction and the cellular transcriptome, providing valuable insights into the pathogenesis of TDP43 proteinopathies.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

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PROVIDER: E-MTAB-13738 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): ERP156983

REPOSITORIES: biostudies-arrayexpress

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Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.

Dataset Information

Comprehensive Transcriptomic Analysis of NSC34 Motor Neurons following TDP43 Modulation: Knockdown vs. Control and Wild Type vs. TDP43 M337V Mutation

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