RNA splicing, ageing, TDP-43 aggregation and neurodegeneration

Abstract

The role of splicing factors in pathological processes is increasingly documented. This is particularly evident in the pathologies affecting the nervous system where either the mis-folding or aggregation of RNA binding proteins is a key event in triggering the neurodegeneration. The aggregation of TDP-43 is the major distinguishing feature of most cases of Amyotrophic Lateral Sclerosis (ALS). There is still a significant uncertainty in regards to many aspects concerning the nature of the aggregates and their functional consequences. The biochemical and genetic aspects of TDP-43 aggregation need further definition, as new therapies could be directed towards them. A better understanding of TDP-43 structure and interactions is needed, from what we currently know it has been possible to construct cellular and animal models of TDP- 43 ALS like aggregation. Using these models drugs that can revert aggregation and recover function have been identified. Finally, ALS is a disease that occurs mostly during the fifth to the seventh decade of life. In this respect, it has been observed that the onset of the locomotion defect in an ALS fly model coincides with an age-related 4-fold drop in TBPH levels (the Drosophila TDP43 orthologous), similar TDP 43 reduction with age was observed in mice brain. Thus, understanding the relationship between aging and TDP-43 production and mis-folding in cell culture, animal models, and human tissues might provide further clues to explain the time of disease onset.