Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.
Highlights
While the genetic basis of 80% of Amyotrophic lateral sclerosis (ALS) is unknown, at least 31 genes, including SOD1 and TARDBP encoding the RNA/DNA-binding protein TDP-43, with mutations associated with ALS have been identified [13, 37]
The disease-onset ages of individual N390D/+ female mice were highly variable as reflected by the rotarod test, and the survival time of N390D/+ female mice was significantly longer than males (Additional file 1: Figure S1d), with average age being 25.5 ± 6 months
Like the heterozygous Q331K/+ mice studied by White et al, [72] the N390D/+ male mice from either line had similar body weight as the +/+ male mice (Additional file 1: Figure S1e) conspicuous weight loss was observed in their remains (Fig. 1c), possibly in part resulted from the lack of nutrition at the end stage of their lives
Summary
While the genetic basis of 80% of ALS is unknown, at least 31 genes, including SOD1 and TARDBP encoding the RNA/DNA-binding protein TDP-43, with mutations associated with ALS have been identified [13, 37]. A total of more than 50 missense mutations have been identified in the TARDBP gene through genetic analysis a number of familial and sporadic ALS cases [10]. More than 95% of all ALS patients (ALS-TDP) are characterized by enhanced cleavage of TDP-43 to generate TDP-35/ TDP-25 fragments, by TDP-43 is a ubiquitously expressed heterogeneous nuclear ribonucleoprotein (hnRNP) protein that localized primarily in the nucleus and required for multiple cellular pathways [11, 36, 38, 69] including RNA metabolism and translation Given these ubiquitous functions, aberrant expression of TDP-43 is likely to lead to multiple pathological consequences. Under pathologic conditions, the total amount of TDP-43 in the
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