Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 8, Pages E736-E745Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222809110
Keywords
neurodegeneration; RNA binding proteins; frontotemporal dementia
Categories
Funding
- Wellcome Trust
- Ludwig Institute for Cancer Research
- University of California San Diego Genetics Training Grant National Institute of General Medical Sciences [T32 GM008666]
- National Institutes of Health Neuroplasticity of Aging Training Grant [T32 AG 000216]
- National Science Foundation Graduate Research Fellowship
- Amyotrophic Lateral Sclerosis Association
- Muscular Dystrophy Association Career Development Award
- National Institutes of Health [NS075449, HG004659, NS075216]
- [NS069144]
- MRC [G0900688, MC_G1000733] Funding Source: UKRI
- Medical Research Council [G0900688, MC_G1000733, G0300329, G0500289B] Funding Source: researchfish
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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.
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