| Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. | |
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MedLine Citation:
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PMID: 23023293 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Clotilde Lagier-Tourenne; Magdalini Polymenidou; Kasey R Hutt; Anthony Q Vu; Michael Baughn; Stephanie C Huelga; Kevin M Clutario; Shuo-Chien Ling; Tiffany Y Liang; Curt Mazur; Edward Wancewicz; Aneeza S Kim; Andy Watt; Sue Freier; Geoffrey G Hicks; John Paul Donohue; Lily Shiue; C Frank Bennett; John Ravits; Don W Cleveland; Gene W Yeo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-09-30 |
Journal Detail:
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Title: Nature neuroscience Volume: 15 ISSN: 1546-1726 ISO Abbreviation: Nat. Neurosci. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-10-29 Completed Date: 2013-01-03 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9809671 Medline TA: Nat Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 1488-97 Citation Subset: IM |
Affiliation:
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Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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GEO/GSE40653 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amyotrophic Lateral Sclerosis
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genetics,
metabolism*,
pathology Animals Brain / metabolism, pathology Carrier Proteins / genetics, metabolism Cell Cycle Proteins / genetics, metabolism Cell Line, Transformed DNA-Binding Proteins / deficiency, genetics, metabolism* Excitatory Amino Acid Transporter 2 / genetics, metabolism Female Frontotemporal Dementia / genetics, metabolism*, pathology Gene Expression Profiling Gene Expression Regulation / genetics Histone-Lysine N-Methyltransferase / metabolism Humans Immunoprecipitation Kv Channel-Interacting Proteins / metabolism Membrane Proteins / metabolism Mice Mice, Inbred C57BL Mice, Knockout Motor Neurons / metabolism Nerve Tissue Proteins / genetics, metabolism Neural Cell Adhesion Molecules / metabolism Neural Stem Cells / metabolism Neurofilament Proteins / metabolism Oligonucleotide Array Sequence Analysis Protein Binding / genetics Protein Structure, Tertiary / genetics RNA Precursors / genetics, metabolism* RNA Splicing / genetics RNA, Messenger / genetics, metabolism* RNA, Small Interfering / genetics, metabolism RNA-Binding Protein FUS / deficiency, genetics, metabolism* Shal Potassium Channels / metabolism Spinal Cord / metabolism Ubiquitin-Protein Ligases / metabolism tau Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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GM084317/GM/NIGMS NIH HHS; HG004659/HG/NHGRI NIH HHS; K99NS075216/NS/NINDS NIH HHS; R01 GM084317/GM/NIGMS NIH HHS; R01 HG004659/HG/NHGRI NIH HHS; R01 NS075449/NS/NINDS NIH HHS; R01NS075449/NS/NINDS NIH HHS; R37NS27036/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Excitatory Amino Acid Transporter 2; 0/KCNIP4 protein, human; 0/Kv Channel-Interacting Proteins; 0/Membrane Proteins; 0/Nerve Tissue Proteins; 0/Neural Cell Adhesion Molecules; 0/Neurofilament Proteins; 0/RNA Precursors; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/RNA-Binding Protein FUS; 0/Shal Potassium Channels; 0/UBQLN1 protein, human; 0/protein TDP-43; 0/tau Proteins; EC 2.1.1.43/Histone-Lysine N-Methyltransferase; EC 2.1.1.43/SMYD2 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/parkin protein |
| Comments/Corrections | |
Comment In:
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Nat Neurosci. 2012 Nov;15(11):1467-9
[PMID:
23103989
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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