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

Journal Article


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Abstract


  • 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.

Publication Date


  • 2017

Citation


  • Zeineddine, R., Farrawell, N. E., Lambert-Smith, I. A. & Yerbury, J. J. (2017). Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation. Cell Stress and Chaperones, 22 (6), 893-902.

Scopus Eid


  • 2-s2.0-85019761697

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2111&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1085

Number Of Pages


  • 9

Start Page


  • 893

End Page


  • 902

Volume


  • 22

Issue


  • 6

Place Of Publication


  • Netherlands

Abstract


  • 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.

Publication Date


  • 2017

Citation


  • Zeineddine, R., Farrawell, N. E., Lambert-Smith, I. A. & Yerbury, J. J. (2017). Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation. Cell Stress and Chaperones, 22 (6), 893-902.

Scopus Eid


  • 2-s2.0-85019761697

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2111&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1085

Number Of Pages


  • 9

Start Page


  • 893

End Page


  • 902

Volume


  • 22

Issue


  • 6

Place Of Publication


  • Netherlands