Influence de TDP-43 sur la régulation de hnRNP A1 : un impact potentiel sur la sclérose latérale amyotrophique
ALS is a fatal and late onset disease characterized by the selective loss of lower and upper motor neurons. Yet, there is no way to robustly slow or cure the disease. Recent discoveries concern TDP-43 and hnRNP A1 where mutations have been identified in ALS cases. Both have multiple functions in RNA metabolism, making the impact of mutations difficult to define. Our hypothesis is that TDP-43 regulates hnRNP A1 and that the ALS causative mutations deregulate this mechanism, having a major impact on the vulnerability of motor neurons. Our results demonstrate that TDP-43 binds hnRNP A1 mRNA, but does not affect its stability. In contrast, TDP-43 represses the expression of hnRNP A1. This mechanism could be applied in vivo where hnRNP A1B/A1 protein ratio increases in aged mice and even more in TDP-43A315T mice in the cervical and lumbar region of the spinal cord. This difference is not caused by a defect in alternative splicing. Also, the TDP-43A315T mutation would be more responsible for this difference than the overexpression of TDP-43 (result from cell culture). The impact of that increased on the cell could be the formation of aggregates since the shape of hnRNP A1B has four more areas of fibrillation than hnRNP A1. Our findings could thus provide a potential mechanism for the formation of cytoplasmic inclusions recognized as one of the main pathological features of ALS.
TDP-43 hnRNP A1 Transcription ALS Alternative splicing Aggregation