Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation

作者：Zeineddine Rafaa; Farrawell Natalie E; Lambert Smith Isabella A; Yerbury Justin J^*

来源：Cell Stress & Chaperones, 2017, 22(6): 893-902.

DOI：10.1007/s12192-017-0804-y

• Protein aggregation
• Propagation
• Prion
• TDP-43
• SOD1
• ALS

ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology.

• 出版日期2017-11