Abstract
Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised TardbpQ101X mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the TardbpQ101X mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp+/Q101X) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp+/Q101X mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of-function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp+/Q101X mice were crossed with the SOD1G93Adl transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the TardbpQ101X mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community.
Highlights
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the degeneration of upper and lower motor neurons, resulting in denervation and atrophy of skeletal muscles, leading to paralysis
Mutations in TARDBP account for approximately 4% of fALS, a smaller proportion than those caused by mutations in superoxide dismutase 1 (SOD1) (10–20%) or the repeat expansion in C9orf72 (40%), these figures vary within different populations [12,13,14,15,16,17]
No TardbpQ101X/Q101X progeny were detected at birth, or between E7.5-11.5 (n = 47 embryos) or earlier at E6.5 (n = 25 embryos; Table 1)
Summary
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the degeneration of upper and lower motor neurons, resulting in denervation and atrophy of skeletal muscles, leading to paralysis. The majority of ALS cases occur sporadically, approximately 10% of cases are familial (fALS) and our understanding of the genetic causes has expanded dramatically over the past few years [2,3]. Genetic and pathological findings suggest ALS lies within a spectrum of diseases including frontotemporal dementia, a neurodegenerative disorder characterised by degeneration and atrophy of specific cortical areas [1,3]. The observation of TDP43 pathology in both sporadic ALS and C9orf patients [5], and other neurodegenerative disorders [18,19], suggests that TDP43 dysfunction may be widely relevant to ALS pathogenesis and neurodegeneration generally. TDP43 pathology is not observed in SOD1-ALS, which has led to the suggestion that divergent disease processes may underlie these forms of ALS. There is evidence for and against an interaction between TDP43 and SOD1 [20,21,22,23,24]
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