Cytotoxic aggregation and amyloid formation by the myostatin precursor protein

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dc.contributor.authorStarck CS
dc.contributor.authorSutherland Smith AJ
dc.date.accessioned2010-12-08T03:25:17Z
dc.date.accessioned2016-03-06T22:26:25Z
dc.date.availableNO_RESTRICTION
dc.date.available2010-12-08T03:25:17Z
dc.date.available2016-03-06T22:26:25Z
dc.date.issued2010
dc.descriptionFunding: This work was funded by Tertiary Education Commission Top Achiever Doctoral and New Zealand Neuromuscular Alliance Henry Kelsey Scholarships to C.S.S. and grants from the Massey University Research Fund and the Palmerston North Medical Research Foundation to A.J.S.-S.. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.description.abstractMyostatin, 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.
dc.identifier.citationStarck, C. S., & Sutherland-Smith, A. J. (2010). Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein. Plos One, 5(2), e9170. doi: 10.1371/journal.pone.0009170
dc.identifier.harvestedMassey_Dark
dc.identifier.harvestedMassey_Dark
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/10179/1969
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.isbasedonPLoS
dc.relation.isformatofhttp://dx.doi.org/10.1371/journal.pone.0009170
dc.subjectMyostatin precursor protein
dc.subjectMuscle disease
dc.subjectAmyloid disorders
dc.subjectMstnPP
dc.subjectSporadic inclusion body myositis
dc.subjectsIBM
dc.subject.otherFields of Research::320000 Medical and Health Sciences::320300 Medical Biochemistry and Clinical Chemistry::320305 Medical biochemistry: proteins and peptides
dc.titleCytotoxic aggregation and amyloid formation by the myostatin precursor protein
dc.typeJournal article
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