Amelioration of protein misfolding disease by rapamycin: translation or autophagy?
Amelioration of protein misfolding disease by rapamycin: translation or autophagy?
Rapamycin is an inhibitor of mTOR, a key component of the mTORC1 complex that controls the growth and survival of cells in response to growth factors, nutrients, energy balance and stresses. The downstream targets of mTORC1 include ribosome biogenesis, transcription, translation and macroautophagy. Recently it was proposed that rapamycin and its derivatives enhance the clearance (and/or reduce the accumulation) of mutant intracellular proteins causing proteinopathies such as tau, alpha-synuclein, ataxin-3, and full-length or fragments of huntingtin containing a polyglutamine (polyQ) expansion, by upregulating macroautophagy. We tested this proposal directly using macroautophagy-deficient fibroblasts. We found that rapamycin inhibits the aggregation of a fragment of huntingtin (exon 1) containing 97 polyQs similarly in macroautophagy-proficient (Atg5(+/+)) and macroautophagy-deficient (Atg5(-/-)) cells. These data demonstrate that autophagy is not the only mechanism by which rapamycin can alleviate the accumulation of misfolded proteins. Our data suggest that rapamycin inhibits mutant huntingtin fragment accumulation due to inhibition of protein synthesis. A model illustrates how a modest reduction in polyQ synthesis can lead to a long-lasting reduction in polyQ aggregation. We propose that several mechanisms exist by which rapamycin reduces the accumulation and potential toxicity of misfolded proteins in diseases caused by protein misfolding and aggregation.
542-545
Wyttenbach, A.
69846a0f-fb60-4a28-84eb-ed865a5e31fa
Hands, S.
55156699-63e7-40d5-a9bc-639c57dd4c82
King, M. A.
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Lipkow, K.
74177d2a-5be1-406a-994a-1667344e32c2
Tolkovsky, A. M.
d9a86297-04b3-4450-9380-debbb9f96957
May 2008
Wyttenbach, A.
69846a0f-fb60-4a28-84eb-ed865a5e31fa
Hands, S.
55156699-63e7-40d5-a9bc-639c57dd4c82
King, M. A.
d22c930f-60d8-4d5b-ab11-6582c987334d
Lipkow, K.
74177d2a-5be1-406a-994a-1667344e32c2
Tolkovsky, A. M.
d9a86297-04b3-4450-9380-debbb9f96957
Wyttenbach, A., Hands, S., King, M. A., Lipkow, K. and Tolkovsky, A. M.
(2008)
Amelioration of protein misfolding disease by rapamycin: translation or autophagy?
Autophagy, 4 (4), .
Abstract
Rapamycin is an inhibitor of mTOR, a key component of the mTORC1 complex that controls the growth and survival of cells in response to growth factors, nutrients, energy balance and stresses. The downstream targets of mTORC1 include ribosome biogenesis, transcription, translation and macroautophagy. Recently it was proposed that rapamycin and its derivatives enhance the clearance (and/or reduce the accumulation) of mutant intracellular proteins causing proteinopathies such as tau, alpha-synuclein, ataxin-3, and full-length or fragments of huntingtin containing a polyglutamine (polyQ) expansion, by upregulating macroautophagy. We tested this proposal directly using macroautophagy-deficient fibroblasts. We found that rapamycin inhibits the aggregation of a fragment of huntingtin (exon 1) containing 97 polyQs similarly in macroautophagy-proficient (Atg5(+/+)) and macroautophagy-deficient (Atg5(-/-)) cells. These data demonstrate that autophagy is not the only mechanism by which rapamycin can alleviate the accumulation of misfolded proteins. Our data suggest that rapamycin inhibits mutant huntingtin fragment accumulation due to inhibition of protein synthesis. A model illustrates how a modest reduction in polyQ synthesis can lead to a long-lasting reduction in polyQ aggregation. We propose that several mechanisms exist by which rapamycin reduces the accumulation and potential toxicity of misfolded proteins in diseases caused by protein misfolding and aggregation.
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Published date: May 2008
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Local EPrints ID: 145331
URI: http://eprints.soton.ac.uk/id/eprint/145331
ISSN: 1554-8627
PURE UUID: 89e992b3-0e0b-46a5-b1e6-c85df017325e
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Date deposited: 19 Apr 2010 09:27
Last modified: 14 Mar 2024 00:50
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Author:
A. Wyttenbach
Author:
S. Hands
Author:
M. A. King
Author:
K. Lipkow
Author:
A. M. Tolkovsky
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