Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is thought to be linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 normally localizes in the nucleus but its main localization shifts to the cytoplasm in most affected cells of ALS and FTLD patients. It is not yet known whether nuclear or cytoplasmic TDP-43 is responsible for TDP-43-induced neurotoxicity. In this study, we show that nuclear TDP-43 causes TDP-43 neurotoxicity. DNA/RNA-binding and dimerization of TDP-43 are both essential for TDP-43-induced cell death. Moreover, endogenous heterogeneous nuclear ribonucleoprotein-U (hnRNP-U) binds to TDP-43 and knocking-down of hnRNP-U induces neurotoxicity, whereas overexpression of hnRNP-U or hnRNP-A2 inhibits TDP-43-induced neurotoxicity. In addition, hnRNP-U inhibits TDP-43-mediated alterations in splicing of POLDIP3 mRNA. Altogether, these results suggest that nuclear TDP-43 becomes neurotoxic by escaping from the inhibitory regulation by hnRNPs.
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PMID:Nuclear TDP-43 causes neuronal toxicity by escaping from the inhibitory regulation by hnRNPs. 2537 56

The full definition of the physiological RNA targets regulated by TDP-43 and FUS RNA-binding proteins (RBPs) represents an important issue in understanding the pathogenic mechanisms associated to these two proteins in amyotrophic lateral sclerosis and frontotemporal dementia. In the last few years several high-throughput screenings have generated a plethora of data, which are difficult to compare due to the different experimental designs and models explored. In this study by using the Affymetrix Exon Arrays, we were able to assess and compare the effects of both TDP-43 and FUS loss-of-function on the whole transcriptome using the same human neuronal SK-N-BE cell model. We showed that TDP-43 and FUS depletion induces splicing and gene expression changes mainly distinct for the two RBPs, although they may regulate common pathways, including neuron differentiation and cytoskeleton organization as evidenced by functional annotation analysis. In particular, TDP-43 and FUS were found to regulate splicing and expression of genes related to neuronal (SEPT6, SULT4A1, TNIK) and RNA metabolism (DICER, ELAVL3/HuC, POLDIP3). Our extended analysis at protein level revealed that these changes have also impact on the protein isoform ratio and content, not always in a direct correlation with transcriptomic data. Contrarily to a loss-of-function mechanism, we showed that mutant TDP-43 proteins maintained their splicing activity in human ALS fibroblasts and experimental cell lines. Our findings further contribute to define the biological functions of these two RBPs in physiological and disease state, strongly encouraging the evaluation of the identified transcriptomic changes at protein level in neuronal experimental models.
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PMID:From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models. 2651 32