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


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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Available from: Kazuo Fushimi
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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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    • "Nevertheless, pure, recombinant, wild type SOD1 can form fibrils spontaneously, while conditions that disrupt its stable dimer, such as reducing agents or high temperature, accelerate the aggregation reaction (Chia et al., 2010; Münch et al., 2011). Also, similarly to TDP-43 (Guo et al., 2011; Johnson et al., 2009), ALS-linked mutations in SOD1 promote aggregation (Chia et al., 2010; Prudencio et al., 2009). In contrast, most of the ALSlinked FUS mutations are localized in the NLS and do not influence aggregation per se, but rather promote redistribution of FUS to the cytoplasm (Dormann et al., 2010; Ito et al., 2011; Sun et al., 2011), which consequently may initiate its aggregate nucleation. "
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    ABSTRACT: Propagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells.
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