Document Detail


Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs.
MedLine Citation:
PMID:  23023293     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
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:
Title:  Nature neuroscience     Volume:  15     ISSN:  1546-1726     ISO Abbreviation:  Nat. Neurosci.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-01-03     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9809671     Medline TA:  Nat Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1488-97     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE40653
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MeSH Terms
Descriptor/Qualifier:
Amyotrophic Lateral Sclerosis / 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:
089701//Wellcome Trust; 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:
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:
Nat Neurosci. 2012 Nov;15(11):1467-9   [PMID:  23103989 ]

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