ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

被引:348
作者
Arnold, Eveline S. [2 ,4 ]
Ling, Shuo-Chien [1 ,2 ,4 ]
Huelga, Stephanie C. [2 ,5 ,6 ]
Lagier-Tourenne, Clotilde [2 ,4 ]
Polymenidou, Magdalini [2 ,4 ]
Ditsworth, Dara [2 ,4 ]
Kordasiewicz, Holly B. [2 ,4 ]
McAlonis-Downes, Melissa [2 ,4 ]
Platoshyn, Oleksandr [3 ,5 ,6 ]
Parone, Philippe A. [2 ,4 ]
Da Cruz, Sandrine [2 ,4 ]
Clutario, Kevin M. [2 ,4 ]
Swing, Debbie [7 ]
Tessarollo, Lino [7 ]
Marsala, Martin [3 ,5 ,6 ]
Shaw, Christopher E. [8 ]
Yeo, Gene W. [2 ,5 ,6 ]
Cleveland, Don W. [1 ,2 ,4 ]
机构
[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Stem Cell Program, La Jolla, CA 92093 USA
[6] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
[7] NCI, Neural Dev Sect, Mouse Canc Genet Program, Frederick, MD 21702 USA
[8] Kings Coll London, Inst Psychiat, MRC, Ctr Neurodegenerat Res, London SE5 8AF, England
基金
美国国家卫生研究院; 英国惠康基金; 美国国家科学基金会;
关键词
neurodegeneration; RNA binding proteins; frontotemporal dementia; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DNA-BINDING PROTEIN-43; TRANSGENIC MICE; SPINAL-CORD; PROCESSING PROTEIN; CELLULAR TOXICITY; TARDBP MUTATIONS; ALPHA-SYNUCLEIN; MUTANT TDP-43;
D O I
10.1073/pnas.1222809110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:E736 / E745
页数:10
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