TDP-43 loss of cellular function through aggregation requires additional structural determinants beyond its C-terminal Q/N prion-like domain.

摘要: TDP-43 aggregates are the neurohistological landmark of diseases like amyotrophic lateral sclerosis and frontotemporal dementia. Their role in pathogenesis these conditions is not yet clear mainly due to lack proper models aggregation that may allow study mechanism formation, their interactions with other cellular components effect on cell metabolism. In this work, we have used tandem repeats prion Q/N-rich region TAR DNA-binding protein (TDP-43) fused additional sequences trigger aggregate formation neuronal non-neuronal lines. At functional level, able sequester endogenous depleting its nuclear levels inducing loss function at pre-mRNA splicing level. No apparent direct toxicity seems be present beyond TDP-43. To our knowledge, only system achieves full TDP 43 depletion effects similar RNAi or gene deletion. As a result, model will prove useful investigate loss-of-function mediated by within cells without affecting expression gene. We identified N-terminus sequence as domain enhances interaction insolubilization. These data show for first time can lead total defective TDP-43-dependent events genes.