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Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein
Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin prec...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820090/ https://www.ncbi.nlm.nih.gov/pubmed/20161792 http://dx.doi.org/10.1371/journal.pone.0009170 |
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author | Starck, Carlene S. Sutherland-Smith, Andrew J. |
author_facet | Starck, Carlene S. Sutherland-Smith, Andrew J. |
author_sort | Starck, Carlene S. |
collection | PubMed |
description | Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis. |
format | Text |
id | pubmed-2820090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28200902010-02-17 Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein Starck, Carlene S. Sutherland-Smith, Andrew J. PLoS One Research Article Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis. Public Library of Science 2010-02-11 /pmc/articles/PMC2820090/ /pubmed/20161792 http://dx.doi.org/10.1371/journal.pone.0009170 Text en Starck, Sutherland-Smith. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Starck, Carlene S. Sutherland-Smith, Andrew J. Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title | Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title_full | Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title_fullStr | Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title_full_unstemmed | Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title_short | Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein |
title_sort | cytotoxic aggregation and amyloid formation by the myostatin precursor protein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820090/ https://www.ncbi.nlm.nih.gov/pubmed/20161792 http://dx.doi.org/10.1371/journal.pone.0009170 |
work_keys_str_mv | AT starckcarlenes cytotoxicaggregationandamyloidformationbythemyostatinprecursorprotein AT sutherlandsmithandrewj cytotoxicaggregationandamyloidformationbythemyostatinprecursorprotein |