SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

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

doi:10.1186/s13024-015-0053-4

SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

63 Citations (Scopus)

40 Downloads (Pure)

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_ex146Q, 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.

Original language	English
Article number	57
Pages (from-to)	1-17
Number of pages	17
Journal	Molecular Neurodegeneration
Volume	10
DOIs	https://doi.org/10.1186/s13024-015-0053-4
Publication status	Published - 31 Oct 2015

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Access to Document

10.1186/s13024-015-0053-4

Publisher version (open access).pdfFinal published version, 2.75 MB

Cite this

Zeineddine, R., Pundavela, J. F., Corcoran, L., Stewart, E. M., Do-Ha, D., Bax, M., Guillemin, G., Vine, K. L., Hatters, 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, 1-17. Article 57. https://doi.org/10.1186/s13024-015-0053-4

@article{2114bd45ce8b428a81eba3555fc3aa98,

title = "SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation",

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, Httex146Q, 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.",

author = "Rafaa Zeineddine and Pundavela, {Jay F.} and Lisa Corcoran and Stewart, {Elise M.} and Dzung Do-Ha and Monique Bax and Gilles Guillemin and Vine, {Kara L.} and Hatters, {Danny M.} and Heath Ecroyd and Dobson, {Christopher M.} and Turner, {Bradley J.} and Lezanne Ooi and Wilson, {Mark R.} and Cashman, {Neil R.} and Yerbury, {Justin J.}",

note = "Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2015",

month = oct,

day = "31",

doi = "10.1186/s13024-015-0053-4",

language = "English",

volume = "10",

pages = "1--17",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "Springer, Springer Nature",

}

Zeineddine, R, Pundavela, JF, Corcoran, L, Stewart, EM, Do-Ha, D, Bax, M, Guillemin, G, Vine, KL, Hatters, DM, Ecroyd, H, Dobson, CM, Turner, BJ, Ooi, L, Wilson, MR, Cashman, NR & Yerbury, JJ 2015, 'SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation', Molecular Neurodegeneration, vol. 10, 57, pp. 1-17. https://doi.org/10.1186/s13024-015-0053-4

TY - JOUR

T1 - SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

AU - Zeineddine, Rafaa

AU - Pundavela, Jay F.

AU - Corcoran, Lisa

AU - Stewart, Elise M.

AU - Do-Ha, Dzung

AU - Bax, Monique

AU - Guillemin, Gilles

AU - Vine, Kara L.

AU - Hatters, Danny M.

AU - Ecroyd, Heath

AU - Dobson, Christopher M.

AU - Turner, Bradley J.

AU - Ooi, Lezanne

AU - Wilson, Mark R.

AU - Cashman, Neil R.

AU - Yerbury, Justin J.

N1 - Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2015/10/31

Y1 - 2015/10/31

N2 - 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, Httex146Q, 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.

AB - 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, Httex146Q, 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.

UR - http://www.scopus.com/inward/record.url?scp=84946499018&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/nhmrc/1003032

UR - http://purl.org/au-research/grants/nhmrc/1008910

UR - http://purl.org/au-research/grants/arc/FT110100586

U2 - 10.1186/s13024-015-0053-4

DO - 10.1186/s13024-015-0053-4

M3 - Article

C2 - 26520394

AN - SCOPUS:84946499018

SN - 1750-1326

VL - 10

SP - 1

EP - 17

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

M1 - 57

ER -

SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this