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

ABSTRACT: TDP-43 aggregates are the neurohistological landmark of diseases like amyotrophic lateral sclerosis and frontotemporal dementia. Their role in the pathogenesis of these conditions is not yet clear mainly due to the lack of proper models of aggregation that may allow the study of the mechanism of formation, their interactions with other cellular components and their effect on the cell metabolism. In this work, we have used tandem repeats of the prion like Q/N-rich region of TAR DNA-binding protein (TDP-43) fused to additional TDP-43 protein sequences to trigger aggregate formation in neuronal and non-neuronal cell lines. At the functional level, these aggregates are able to sequester endogenous TDP-43 depleting its nuclear levels and inducing loss of function at the pre-mRNA splicing level.

SUBMITTER: Budini M 

PROVIDER: S-EPMC4262490 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature