Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy, Vinod, Walker, Adam K., Yerbury, Justin, Soo, Kai Ying, Farg, Manal A., Hoang, Vy, Zeineddine, Rafaa, Spencer, Damian and Atkin, Julie D. (2013) Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells. Cellular and Molecular Life Sciences, 70 21: 4181-4195. doi:10.1007/s00018-013-1385-2


Author Sundaramoorthy, Vinod
Walker, Adam K.
Yerbury, Justin
Soo, Kai Ying
Farg, Manal A.
Hoang, Vy
Zeineddine, Rafaa
Spencer, Damian
Atkin, Julie D.
Title Extracellular wildtype and mutant SOD1 induces ER-Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells
Journal name Cellular and Molecular Life Sciences   Check publisher's open access policy
ISSN 1420-682X
1420-9071
Publication date 2013-11-01
Sub-type Article (original research)
DOI 10.1007/s00018-013-1385-2
Open Access Status Not yet assessed
Volume 70
Issue 21
Start page 4181
End page 4195
Total pages 15
Place of publication Basel, Switzerland
Publisher Birkhaeuser Science
Language eng
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER-Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS.
Keyword ALS
Endoplasmic reticulum
Extracellular
Golgi
SOD1
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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