Article

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

State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 06/2011; 18(7):822-30. DOI: 10.1038/nsmb.2053
Source: PubMed

ABSTRACT 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.

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    • "This seems to be true also in several cellular models, from yeast to mammalian cells. The above mentioned study by Johnson et al. shows that in a yeast model expressing wt or mutant forms of TDP-43, the latter gave rise to more numerous aggregates than the wt (Johnson et al., 2009) and the same was observed in HEK293 cells and mammalian cultured neurons expressing wt and mutant TDP-43 (Guo et al., 2011). Going a step further, Furukawa and collaborators showed that in vitro produced TDP-43 fibrils could seed aggregation when transduced into TDP- 43 expressing HEK293 cells and much less efficiently in human neuroblastoma cells, confirming the seeding ability observed previously in vitro (Furukawa et al., 2011). "
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    • "? TDP-43 ALS; FTD Yes (Guo et al., 2011; Fang et al., 2014 (A315T variant "
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    • "Inhibiting or stabilizing this interaction is proposed to cause degradation to 25 kDa or oligomerization respectively. This segment of protein also confers structural betasheet conformations that appear to promote the formation of amyloid fibrils, and this propensity is enhanced by the A315T mutation found in familial ALS (Guo et al., 2011). Thus, function and pathogenicity may be two sides of the same coin, and the prion nature of TDP-43 opens up the intriguing possibility of prion-like spreading of disease (Nonaka et al., 2013). "
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