TDP-43 enhances translation of specific mRNAs linked to neurodegenerative disease
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TDP-43 enhances translation of specific mRNAs linked to neurodegenerative disease. / Neelagandan, Nagammal; Gonnella, Giorgio; Dang, Stefan; Janiesch, Philipp C; Miller, Katharine K; Küchler, Katrin; Marques, Rita F; Indenbirken, Daniela; Alawi, Malik; Grundhoff, Adam; Kurtz, Stefan; Duncan, Kent E.
in: NUCLEIC ACIDS RES, Jahrgang 47, Nr. 1, 10.01.2019, S. 341-361.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - TDP-43 enhances translation of specific mRNAs linked to neurodegenerative disease
AU - Neelagandan, Nagammal
AU - Gonnella, Giorgio
AU - Dang, Stefan
AU - Janiesch, Philipp C
AU - Miller, Katharine K
AU - Küchler, Katrin
AU - Marques, Rita F
AU - Indenbirken, Daniela
AU - Alawi, Malik
AU - Grundhoff, Adam
AU - Kurtz, Stefan
AU - Duncan, Kent E
PY - 2019/1/10
Y1 - 2019/1/10
N2 - The RNA-binding protein TDP-43 is heavily implicated in neurodegenerative disease. Numerous patient mutations in TARDBP, the gene encoding TDP-43, combined with data from animal and cell-based models, imply that altered RNA regulation by TDP-43 causes Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. However, underlying mechanisms remain unresolved. Increased cytoplasmic TDP-43 levels in diseased neurons suggest a possible role in this cellular compartment. Here, we examined the impact on translation of overexpressing human TDP-43 and the TDP-43A315T patient mutant protein in motor neuron-like cells and primary cultures of cortical neurons. In motor-neuron like cells, TDP-43 associates with ribosomes without significantly affecting global translation. However, ribosome profiling and additional assays revealed enhanced translation and direct binding of Camta1, Mig12, and Dennd4a mRNAs. Overexpressing either wild-type TDP-43 or TDP-43A315T stimulated translation of Camta1 and Mig12 mRNAs via their 5'UTRs and increased CAMTA1 and MIG12 protein levels. In contrast, translational enhancement of Dennd4a mRNA required a specific 3'UTR region and was specifically observed with the TDP-43A315T patient mutant allele. Our data reveal that TDP-43 can function as an mRNA-specific translational enhancer. Moreover, since CAMTA1 and DENND4A are linked to neurodegeneration, they suggest that this function could contribute to disease.
AB - The RNA-binding protein TDP-43 is heavily implicated in neurodegenerative disease. Numerous patient mutations in TARDBP, the gene encoding TDP-43, combined with data from animal and cell-based models, imply that altered RNA regulation by TDP-43 causes Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. However, underlying mechanisms remain unresolved. Increased cytoplasmic TDP-43 levels in diseased neurons suggest a possible role in this cellular compartment. Here, we examined the impact on translation of overexpressing human TDP-43 and the TDP-43A315T patient mutant protein in motor neuron-like cells and primary cultures of cortical neurons. In motor-neuron like cells, TDP-43 associates with ribosomes without significantly affecting global translation. However, ribosome profiling and additional assays revealed enhanced translation and direct binding of Camta1, Mig12, and Dennd4a mRNAs. Overexpressing either wild-type TDP-43 or TDP-43A315T stimulated translation of Camta1 and Mig12 mRNAs via their 5'UTRs and increased CAMTA1 and MIG12 protein levels. In contrast, translational enhancement of Dennd4a mRNA required a specific 3'UTR region and was specifically observed with the TDP-43A315T patient mutant allele. Our data reveal that TDP-43 can function as an mRNA-specific translational enhancer. Moreover, since CAMTA1 and DENND4A are linked to neurodegeneration, they suggest that this function could contribute to disease.
KW - Journal Article
U2 - 10.1093/nar/gky972
DO - 10.1093/nar/gky972
M3 - SCORING: Journal article
C2 - 30357366
VL - 47
SP - 341
EP - 361
JO - NUCLEIC ACIDS RES
JF - NUCLEIC ACIDS RES
SN - 0305-1048
IS - 1
ER -