TDP-43 expression in mouse models of amyotrophic lateral sclerosis and spinal muscular atrophy

TDP-43 mislocalisation to ubiquitinated inclusions or cytoplasm was notably lacking in anterior horn cells from transgenic mutant SOD1G93A mice. In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain. Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the commonest forms of human motor neuron disease in children and adults, respectively. The disorders share the feature of vulnerability of lower motor neurons in the anterior horn of the spinal cord, implicating possible common factors in motor neuron degeneration. ALS also affects upper motor neurons in the cerebral cortex, and a proportion of cases demonstrate more widespread changes that overlap pathologically and clinically with frontotemporal lobar degeneration (FTLD). While SMA is an autosomal recessive genetic disorder caused by deletions of the survival motor neuron 1 (SMN1) gene with resulting SMN deficiency [1], only about 5–10% of ALS cases are familial (fALS) [2,3]. Dominant mutations in the superoxide dismutase 1 gene (SOD1) cause approximately 20% of the familial cases, and thus contribute the largest single group of hereditary ALS. The genetic contribution of single genes or at risk haplotypes to the majority of sporadic cases is currently thought to be modest [4]. Novel insights into the aetiopathogenesis of ALS have come from the discovery of the TAR DNA binding protein (TDP-43) as a major constituent of the characteristic ubiquitinated inclusions found in