Molecular Brain · 2020 · 68 citations · 7 references
Life SciencesNeurologyNeuroscienceMolecular NeurobiologyMolecular NeuroscienceNeurodegenerationAmyotrophic Lateral SclerosisMolecular Basis Of NeurodegenerationMolecular NeurogeneticsNeurodegenerative DiseasesNeurodegenerative DisordersNeurogenetic DisordersAmyotrophic Lateral Sclerosis ModelsAmyotrophic Lateral Sclerosis PathologyMissense MutationsRna Splicing In NeuronsRodent NeurodegenerationSporadic Amyotrophic Lateral SclerosisTar Dna-binding Protein 43 PathologyTardbp Mutations
Abstract Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is a pathological signature of amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found in inherited and sporadic ALS, indicating that dysfunction in TDP-43 is causative for ALS. To model TDP-43-linked ALS in rodents, we generated TDP-43 knock-in mice with inherited ALS patient-derived TDP-43 M337V mutation. Homozygous TDP-43 M337V mice developed normally without exhibiting detectable motor dysfunction and neurodegeneration. However, splicing of mRNAs regulated by TDP-43 was deregulated in the spinal cords of TDP-43 M337V mice. Together with the recently reported TDP-43 knock-in mice with ALS-linked mutations, our finding indicates that ALS patient-derived mutations in the TARDBP gene at a carboxyl-terminal domain of TDP-43 may cause a gain of splicing function by TDP-43, however, were insufficient to induce robust neurodegeneration in mice.
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Spliceosome integrity is defective in the motor neuron diseases ALS and SMA
Hitomi Tsuiji, Yohei Iguchi, Asako Furuya et al. · EMBO Molecular Medicine · 2012 · 208 citations · Full text