Familial Parkinson disease mutations influence α-synuclein assembly

Ono, Kenjiro; Ikeda, Tokuhei; Takasaki, Jun-ichi; Yamada, Masahito

doi:10.1016/j.nbd.2011.05.025

Cited by 66 publications

(90 citation statements)

References 63 publications

(95 reference statements)

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“…17,19 Our results agree with those experiments that reported an increased β-sheet conformation for the E46K mutant-type rather than wild-type αS. 17,19,25 Moreover, we identify that this increase in β-sheet conformation occurs in the N-terminal and in the C-terminal regions of the E46K mutanttype αS. The most preferred transition to a β-sheet conformation for these residues occurs from a coil structure based on our thermodynamic calculations ( Figure 2).…”

Section: ■ Results and Discussionsupporting

confidence: 91%

“…25 Furthermore, E46K mutant-type αS is reported to convert to β-sheet conformations more readily than the wildtype αS. 17,19 Our results agree with those experiments that reported an increased β-sheet conformation for the E46K mutant-type rather than wild-type αS. 17,19,25 Moreover, we identify that this increase in β-sheet conformation occurs in the N-terminal and in the C-terminal regions of the E46K mutanttype αS.…”

Section: ■ Results and Discussionsupporting

confidence: 89%

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Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Wise-Scira

Dunn

Aloglu

et al. 2013

ACS Chem. Neurosci.

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The E46K genetic missense mutation of the wild-type α-synuclein protein was recently identified in a family of Spanish origin with hereditary Parkinson's disease. Detailed understanding of the structures of the monomeric E46K mutant-type α-synuclein protein as well as the impact of the E46K missense mutation on the conformations and free energy landscapes of the wild-type α-synuclein are required for gaining insights into the pathogenic mechanism of Parkinson's disease. In this study, we use extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations to assess the secondary and tertiary structural properties as well as the conformational preferences of the monomeric wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment. We also present the residual secondary structure component conversion stabilities with dynamics using a theoretical strategy, which we most recently developed. To the best of our knowledge, this study presents the first detailed comparison of the structural and thermodynamic properties of the wild-type and E46K mutant-type α-synuclein proteins in an aqueous solution environment at the atomic level with dynamics. We find that the E46K mutation results not only in local but also in long-range changes in the structural properties of the wild-type α-synuclein protein. The mutation site shows a significant decrease in helical content as well as a large increase in β-sheet structure formation upon E46K mutation. In addition, the β-sheet content of the C-terminal region increases significantly in the E46K mutant-type αS in comparison to the wild-type αS. Our theoretical strategy developed to assess the thermodynamic preference of secondary structure transitions indicates that this shift in secondary structure is the result of a decrease in the thermodynamic preference of turn to helix conversions while the coil to β-sheet preference increases for these residues. Long-range intramolecular protein interactions of the C-terminal with the N-terminal and NAC regions increase upon E46K mutation, resulting in more compact structures for the E46K mutant-type rather than wild-type αS. However, the E46K mutant-type αS structures are less stable than the wild-type αS. Overall, our results show that the E46K mutant-type αS has a higher propensity to aggregate than the wild-type αS and that the N-terminal and C-terminal regions are reactive toward fibrillization and aggregation upon E46K mutation and we explain the associated reasons based on the structural properties herein. Small molecules or drugs that can block the specific residues forming abundant β-sheet structure, which we report here, might help to reduce the reactivity of these intrinsically disordered fibrillogenic proteins toward aggregation and their toxicity.

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Section: ■ Results and Discussionsupporting

confidence: 91%

Section: ■ Results and Discussionsupporting

confidence: 89%

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Wise-Scira

Dunn

Aloglu

et al. 2013

ACS Chem. Neurosci.

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“…In PD, mutations in AS or multiplication of the SNCA gene encoding AS, result in a phenotype of cellular inclusions, cell death, and brain dysfunctions, and familial (f ) PD mutations influence AS assembly [199,200].…”

Section: The Role Of α-Synuclein Mutationsmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…The helical and β-sheet structure formations have been proposed to play crucial roles in the aggregation process of intrinsically disordered fibrillogenic proteins at the center of neurodegenerative diseases. 12,14,24,41 Within the N-terminal region (Met1-Lys60) of the wild-type and A30P mutant-type αS, we detect abundant α-helix formation at Ala19-Lys23 and 3 10 -helix formation at Val15-Ala18, Glu20-Thr22, Gly41-Thr44, and Thr54-Lys60 varying between 20% and 35% ( Figure 1). Interestingly, Gly7-Glu13, Val15-Ala17, Lys32-Val40, and Lys43-Gly47 adopt more prominent helical structure (α-helix or 3 10 -helix; up to 30%) in the structures of the A30P mutanttype than in those of the wild-type αS protein.…”

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confidence: 94%

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

Wise-Scira¹,

Aloglu²,

Dunn³

et al. 2013

ACS Chem. Neurosci.

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The genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type α-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type α-synuclein protein. The β-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type α-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for β-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type α-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type α-synuclein tendency toward aggregation is higher than the wild-type α-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type α-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC-and C-terminal regions of the A30P mutant-type α-synuclein protein might help to reduce the toxicity of the A30P mutant-type α-synuclein protein.

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Familial Parkinson disease mutations influence α-synuclein assembly

Cited by 66 publications

References 63 publications

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

Structures of the E46K Mutant-Type α-Synuclein Protein and Impact of E46K Mutation on the Structures of the Wild-Type α-Synuclein Protein

The role of α-synuclein in neurodegeneration — An update

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

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