Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative condition, which results in death. TDP-43, has been implicated in sALS and fALS, as well as fronto temporal dementia with ubiquitinated inclusions (FTLD-U). Loss of TDP-43 function has been associated with early lethality during embryogenesis of both mice and drosophila models. Fibroblasts obtained from the patients carrying mutations in the TARDBP gene provide a vital tool in investigation of TDP-43 in ALS at native levels of the mutant protein. Here we show that fibroblasts obtained from cases with mutations in TARDBP gene have similar pathological correlates to surviving motor neurons in pathological samples of ALS cases. In keeping with the findings in post mortem material from ALS cases, relative clearing of nuclear TDP-43 was noted in mTDP-43 fibroblasts (p<0.001). mTDP-43 fibroblasts also showed accumulation of p62 positive aggregates (p<0.0003), suggesting that mTDP-43 fibroblasts share some characteristics of the affected motor neurons from both sALS and fALS. Following exogenous stress, TDP-43 localised to HUR positive stress granules (p<0.01), however the formation and disaggregation of stress granules was significantly altered in mTDP-43 cases suggesting that mutation of TDP-43 dysregulates stress handling pathways. We suggest that this may contribute to the premature degeneration of mTDP-43-expressing motor neurons in ALS patients. TDP-43 is also important in the development and maintenance of the motor system in the zebrafish. The TILLED tardbp mutant shows evidence of an MND phenotype and motor behavioural changes which will be described.
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