Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs
Top Cited Papers
- 30 September 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 15 (11), 1488-1497
- https://doi.org/10.1038/nn.3230
Abstract
In this study, the authors compare the RNA binding patterns of FUS/TLS and TDP-43. Although these proteins regulate the processing of mostly distinct gene products, they do show concurrent regulation of a subset of neuronal transcripts that all have exceptionally long introns. FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell–derived human neurons and in TDP-43 aggregate–containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.Keywords
This publication has 61 references indexed in Scilit:
- Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin SynthesisNeuron, 2012
- Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP ProteinsCell Reports, 2012
- Understanding the role of TDP-43 and FUS/TLS in ALS and beyondCurrent Opinion in Neurobiology, 2011
- Single-Molecule mRNA Decay Measurements Reveal Promoter- Regulated mRNA Stability in YeastCell, 2011
- Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP dataNature Biotechnology, 2011
- Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutationActa Neuropathologica, 2011
- A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem CellsCell, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcriptionNature, 2008
- TDP‐43 A315T mutation in familial motor neuron diseaseAnnals of Neurology, 2008