An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity

The TARDBP gene encodes TDP-43, a multifunctional DNA- and RNA-binding protein involved in many cellular processes. Mutations in TARDBP are associated with TDP-43 proteinopathies. In vivo and in vitro studies of mutants and peptides show similarities between TDP-43 and prion proteins, suggesting that TDP-43 derivatives may cause disease by spreading to neighboring neurons. Mutations in TARDBP, encoding TAR DNA-binding protein-43 (TDP-43), are associated with TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We compared wild-type TDP-43 and an ALS-associated mutant TDP-43 in vitro and in vivo. The A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease-resistant fragments. The C terminus of TDP-43 shows sequence similarity to prion proteins. Synthetic peptides flanking residue 315 form amyloid fibrils in vitro and cause neuronal death in primary cultures. These data provide evidence for biochemical similarities between TDP-43 and prion proteins, raising the possibility that TDP-43 derivatives may cause spreading of the disease phenotype among neighboring neurons. Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies.