Int. J. Mol. Sci. 2013, 14(9), 19128-19145; doi:10.3390/ijms140919128
Article

Small Molecules Present in the Cerebrospinal Fluid Metabolome Influence Superoxide Dismutase 1 Aggregation

1email, 1email, 2,3email and 1,* email
Received: 2 August 2013; in revised form: 28 August 2013 / Accepted: 30 August 2013 / Published: 17 September 2013
(This article belongs to the Special Issue Protein Folding 2015)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Superoxide dismutase 1 (SOD1) aggregation is one of the pathological markers of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The underlying molecular grounds of SOD1 pathologic aggregation remains obscure as mutations alone are not exclusively the cause for the formation of protein inclusions. Thus, other components in the cell environment likely play a key role in triggering SOD1 toxic aggregation in ALS. Recently, it was found that ALS patients present a specific altered metabolomic profile in the cerebrospinal fluid (CSF) where SOD1 is also present and potentially interacts with metabolites. Here we have investigated how some of these small molecules affect apoSOD1 structure and aggregation propensity. Our results show that as co-solvents, the tested small molecules do not affect apoSOD1 thermal stability but do influence its tertiary interactions and dynamics, as evidenced by combined biophysical analysis and proteolytic susceptibility. Moreover, these compounds influence apoSOD1 aggregation, decreasing nucleation time and promoting the formation of larger and less soluble aggregates, and in some cases polymeric assemblies apparently composed by spherical species resembling the soluble native protein. We conclude that some components of the ALS metabolome that shape the chemical environment in the CSF may influence apoSOD1 conformers and aggregation.
Keywords: protein aggregation; amyloid; neurodegeneration; nanoparticle tracking analysis; transmission electron microscopy; dynamic light scattering; small molecules
PDF Full-text Download PDF Full-Text [906 KB, uploaded 19 June 2014 05:09 CEST]

Export to BibTeX |
EndNote


MDPI and ACS Style

Cristóvão, J.S.; Leal, S.S.; Cardoso, I.; Gomes, C.M. Small Molecules Present in the Cerebrospinal Fluid Metabolome Influence Superoxide Dismutase 1 Aggregation. Int. J. Mol. Sci. 2013, 14, 19128-19145.

AMA Style

Cristóvão JS, Leal SS, Cardoso I, Gomes CM. Small Molecules Present in the Cerebrospinal Fluid Metabolome Influence Superoxide Dismutase 1 Aggregation. International Journal of Molecular Sciences. 2013; 14(9):19128-19145.

Chicago/Turabian Style

Cristóvão, Joana S.; Leal, Sónia S.; Cardoso, Isabel; Gomes, Cláudio M. 2013. "Small Molecules Present in the Cerebrospinal Fluid Metabolome Influence Superoxide Dismutase 1 Aggregation." Int. J. Mol. Sci. 14, no. 9: 19128-19145.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert