title: ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.
abstract: Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.
authors: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Eveline S
authors: ES
authors: Arnold
authors: Shuo-Chien
authors: SC
authors: Ling
authors: Stephanie C
authors: SC
authors: Huelga
authors: Clotilde
authors: C
authors: Lagier-Tourenne
authors: Magdalini
authors: M
authors: Polymenidou
authors: Dara
authors: D
authors: Ditsworth
authors: Holly B
authors: HB
authors: Kordasiewicz
authors: Melissa
authors: M
authors: McAlonis-Downes
authors: Oleksandr
authors: O
authors: Platoshyn
authors: Philippe A
authors: PA
authors: Parone
authors: Sandrine
authors: S
authors: Da Cruz
authors: Kevin M
authors: KM
authors: Clutario
authors: Debbie
authors: D
authors: Swing
authors: Lino
authors: L
authors: Tessarollo
authors: Martin
authors: M
authors: Marsala
authors: Christopher E
authors: CE
authors: Shaw
authors: Gene W
authors: GW
authors: Yeo
authors: Don W
authors: DW
authors: Cleveland
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012326:RNA Splicing; D060888:Real-Time Polymerase Chain Reaction; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse
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