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SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

Journal Article


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Abstract


  • Background

    Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated.

    Results

    We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Htt ex1 46Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed.

    Conclusion

    Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.

Authors


  •   Zeineddine, Rafaa
  •   Pundavela, Jay (external author)
  •   Corcoran, Lisa (external author)
  •   Stewart, Elise M. (external author)
  •   Do-Ha, Dzung (external author)
  •   Bax, Monique (external author)
  •   Guillemin, Gilles (external author)
  •   Vine, Kara L.
  •   Danny, Danny M. (external author)
  •   Ecroyd, Heath
  •   Dobson, Christopher M. (external author)
  •   Turner, Bradley J. (external author)
  •   Ooi, Lezanne
  •   Mark R Wilson
  •   Cashman, Neil R. (external author)
  •   Yerbury, Justin J.

Publication Date


  • 2015

Citation


  • Zeineddine, R., Pundavela, J. F., Corcoran, L. F., Stewart, E. M., Do-Ha, D., Bax, M., Guillemin, G., Vine, K. L., Danny, D. M., Ecroyd, H., Dobson, C. M., Turner, B. J., Ooi, L., Wilson, M. R., Cashman, N. R. & Yerbury, J. J. (2015). SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation. Molecular Neurodegeneration, 10 (October), 57-1-57-17.

Scopus Eid


  • 2-s2.0-84946499018

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4329&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3306

Has Global Citation Frequency


Start Page


  • 57-1

End Page


  • 57-17

Volume


  • 10

Issue


  • October

Place Of Publication


  • United Kingdom

Abstract


  • Background

    Amyotrophic Lateral Sclerosis is characterized by a focal onset of symptoms followed by a progressive spread of pathology that has been likened to transmission of infectious prions. Cell-to-cell transmission of SOD1 protein aggregates is dependent on fluid-phase endocytosis pathways, although the precise molecular mechanisms remain to be elucidated.

    Results

    We demonstrate in this paper that SOD1 aggregates interact with the cell surface triggering activation of Rac1 and subsequent membrane ruffling permitting aggregate uptake via stimulated macropinocytosis. In addition, other protein aggregates, including those associated with neurodegenerative diseases (TDP-43, Htt ex1 46Q, α-synuclein) also trigger membrane ruffling to gain entry into the cell. Aggregates are able to rupture unstructured macropinosomes to enter the cytosol allowing propagation of aggregation to proceed.

    Conclusion

    Thus, we conclude that in addition to basic proteostasis mechanisms, pathways involved in the activation of macropinocytosis are key determinants in the spread of pathology in these misfolding diseases.

Authors


  •   Zeineddine, Rafaa
  •   Pundavela, Jay (external author)
  •   Corcoran, Lisa (external author)
  •   Stewart, Elise M. (external author)
  •   Do-Ha, Dzung (external author)
  •   Bax, Monique (external author)
  •   Guillemin, Gilles (external author)
  •   Vine, Kara L.
  •   Danny, Danny M. (external author)
  •   Ecroyd, Heath
  •   Dobson, Christopher M. (external author)
  •   Turner, Bradley J. (external author)
  •   Ooi, Lezanne
  •   Mark R Wilson
  •   Cashman, Neil R. (external author)
  •   Yerbury, Justin J.

Publication Date


  • 2015

Citation


  • Zeineddine, R., Pundavela, J. F., Corcoran, L. F., Stewart, E. M., Do-Ha, D., Bax, M., Guillemin, G., Vine, K. L., Danny, D. M., Ecroyd, H., Dobson, C. M., Turner, B. J., Ooi, L., Wilson, M. R., Cashman, N. R. & Yerbury, J. J. (2015). SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation. Molecular Neurodegeneration, 10 (October), 57-1-57-17.

Scopus Eid


  • 2-s2.0-84946499018

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4329&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3306

Has Global Citation Frequency


Start Page


  • 57-1

End Page


  • 57-17

Volume


  • 10

Issue


  • October

Place Of Publication


  • United Kingdom