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Human beta-synuclein rendered fibrillogenic by designed mutations.

ABSTRACT: Filamentous inclusions made of ?-synuclein are found in nerve cells and glial cells in a number of human neurodegenerative diseases, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. The assembly and spreading of these inclusions are likely to play an important role in the etiology of common dementias and movement disorders. Both ?-synuclein and the homologous ?-synuclein are abundantly expressed in the central nervous system; however, ?-synuclein is not present in the pathological inclusions. Previously, we observed a poor correlation between filament formation and the presence of residues 73-83 of ?-synuclein, which are absent in ?-synuclein. Instead, filament formation correlated with the mean ?-sheet propensity, charge, and hydrophilicity of the protein (global physicochemical properties) and ?-strand contiguity calculated by a simple algorithm of sliding averages (local physicochemical property). In the present study, we rendered ?-synuclein fibrillogenic via one set of point mutations engineered to enhance global properties and a second set engineered to enhance predominantly ?-strand contiguity. Our findings show that the intrinsic physicochemical properties of synucleins influence their fibrillogenic propensity via two distinct but overlapping modalities. The implications for filament formation and the pathogenesis of neurodegenerative diseases are discussed.

SUBMITTER: Zibaee S

PROVIDER: S-EPMC2992288 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Human beta-synuclein rendered fibrillogenic by designed mutations.

Zibaee Shahin S Fraser Graham G Jakes Ross R Owen David D Serpell Louise C LC Crowther R Anthony RA Goedert Michel M

The Journal of biological chemistry 20100910 49

Filamentous inclusions made of α-synuclein are found in nerve cells and glial cells in a number of human neurodegenerative diseases, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. The assembly and spreading of these inclusions are likely to play an important role in the etiology of common dementias and movement disorders. Both α-synuclein and the homologous β-synuclein are abundantly expressed in the central nervous system; however, β-synuclein is not presen ...[more]

PMID: 20833719

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Project description:Background. Amyloid secondary structure relies on the intermolecular assembly of polypeptide chains through main-chain interaction. According to this, all proteins have the potential to form amyloid structure, nevertheless, in nature only few proteins aggregate into toxic or functional amyloids. Structural characteristics differ greatly among amyloid proteins reported, so it has been difficult to link the fibrillogenic propensity with structural topology. However, there are ubiquitous topologies not represented in the amyloidome that could be considered as amyloid-resistant attributable to structural features, such is the case of TIM barrel topology. Methods. This work was aimed to study the fibrillogenic propensity of human triosephosphate isomerase (HsTPI) as a model of TIM barrels. In order to do so, aggregation of HsTPI was evaluated under native-like and destabilizing conditions. Fibrillogenic regions were identified by bioinformatics approaches, protein fragmentation and peptide aggregation. Results. We identified four fibrillogenic regions in the HsTPI corresponding to the ?3, ?6, ?7 y ?8 of the TIM barrel. From these, the ?3-strand region (residues 59-66) was highly fibrillogenic. In aggregation assays, HsTPI under native-like conditions led to amorphous assemblies while under partially denaturing conditions (urea 3.2 M) formed more structured aggregates. This slightly structured aggregates exhibited residual cross-? structure, as demonstrated by the recognition of the WO1 antibody and ATR-FTIR analysis. Discussion. Despite the fibrillogenic regions present in HsTPI, the enzyme maintained under native-favoring conditions displayed low fibrillogenic propensity. This amyloid-resistance can be attributed to the three-dimensional arrangement of the protein, where ?-strands, susceptible to aggregation, are protected in the core of the molecule. Destabilization of the protein structure may expose inner regions promoting ?-aggregation, as well as the formation of hydrophobic disordered aggregates. Being this last pathway kinetically favored over the thermodynamically more stable fibril aggregation pathway.

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Human beta-synuclein rendered fibrillogenic by designed mutations.

Publications

Human beta-synuclein rendered fibrillogenic by designed mutations.

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