Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity
Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity
Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
Amyotrophic Lateral Sclerosis/genetics, Cell Line, Cell Survival, HSP70 Heat-Shock Proteins/genetics, Humans, Inclusion Bodies/genetics, Proteasome Endopeptidase Complex, Protein Folding, Superoxide Dismutase/genetics, Superoxide Dismutase-1
15811-6
Weisberg, Sarah J
961a0d27-4c6f-4b4f-badd-ecbf5a828abb
Lyakhovetsky, Roman
dd9f00c5-a583-4a79-a61a-b3088fa6e380
Werdiger, Ayelet-chen
8731ad96-7c88-4edc-876b-c5ef71e4de91
Gitler, Aaron D
e7b1a6f4-19eb-4e55-9203-19d6d1346a8b
Soen, Yoav
bfb0ddae-9311-4ac3-8645-881e476bdde4
Kaganovich, Daniel
ebb13f4e-e925-4aef-88e7-ddc25ef52d8f
25 September 2012
Weisberg, Sarah J
961a0d27-4c6f-4b4f-badd-ecbf5a828abb
Lyakhovetsky, Roman
dd9f00c5-a583-4a79-a61a-b3088fa6e380
Werdiger, Ayelet-chen
8731ad96-7c88-4edc-876b-c5ef71e4de91
Gitler, Aaron D
e7b1a6f4-19eb-4e55-9203-19d6d1346a8b
Soen, Yoav
bfb0ddae-9311-4ac3-8645-881e476bdde4
Kaganovich, Daniel
ebb13f4e-e925-4aef-88e7-ddc25ef52d8f
Weisberg, Sarah J, Lyakhovetsky, Roman, Werdiger, Ayelet-chen, Gitler, Aaron D, Soen, Yoav and Kaganovich, Daniel
(2012)
Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.
Proceedings of the National Academy of Sciences of the United States of America, 109 (39), .
(doi:10.1073/pnas.1205829109).
Abstract
Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
This record has no associated files available for download.
More information
Published date: 25 September 2012
Additional Information:
Freely available online through the PNAS open access option
Keywords:
Amyotrophic Lateral Sclerosis/genetics, Cell Line, Cell Survival, HSP70 Heat-Shock Proteins/genetics, Humans, Inclusion Bodies/genetics, Proteasome Endopeptidase Complex, Protein Folding, Superoxide Dismutase/genetics, Superoxide Dismutase-1
Identifiers
Local EPrints ID: 474177
URI: http://eprints.soton.ac.uk/id/eprint/474177
ISSN: 0027-8424
PURE UUID: 2935560f-a89b-4a98-951e-682aa74af6fe
Catalogue record
Date deposited: 14 Feb 2023 18:02
Last modified: 17 Mar 2024 04:17
Export record
Altmetrics
Contributors
Author:
Sarah J Weisberg
Author:
Roman Lyakhovetsky
Author:
Ayelet-chen Werdiger
Author:
Aaron D Gitler
Author:
Yoav Soen
Author:
Daniel Kaganovich
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics