Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

Uversky, Vladimir N.

doi:10.12688/f1000research.10536.1

Cited by 48 publications

(37 citation statements)

References 200 publications

(203 reference statements)

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“…Although the N-terminal region directly interacts with the C-terminal region, but not the central NAC region, (57), N-terminal truncation also increases the ratio of ␤-sheet structure within ␣S fibrils (56). Recent studies have shown that familial PD-related mutations located in the N-terminal region influence the relative stability of the fibrils and their conformational preferences, rather than the global fibril structures (60,61).…”

Section: Truncation Induces ␣-Synuclein Fibril Polymorphsmentioning

confidence: 99%

The effect of truncation on prion-like properties of α-synuclein

Terada

Suzuki

Nonaka

et al. 2018

Journal of Biological Chemistry

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Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson's disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS's propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS , in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue-truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue-truncated fibrils displayed enhanced seeding activity Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies.

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Section: Truncation Induces ␣-Synuclein Fibril Polymorphsmentioning

confidence: 99%

The effect of truncation on prion-like properties of α-synuclein

Terada

Suzuki

Nonaka

et al. 2018

Journal of Biological Chemistry

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“…Since protein multifunctionality is commonly associated with the presence of intrinsic disorder [22,27,[131][132][133][134][135], and since many viral proteins contain functional IDPRs [13,14,[41][42][43][44][45][46][47], we conducted comprehensive computational analysis of the mature ALKV proteins utilizing a set of commonly used disorder predictors. Results of this analysis are shown in Fig.…”

Section: Intrinsic Disorder and Functionality Of Mature Alkv Proteinsmentioning

confidence: 99%

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

Redwan

Aljaddawi

Uversky

2018

Cell. Mol. Life Sci.

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Infection by the Alkhurma virus (ALKV) leading to the Alkhurma hemorrhagic fever is a common thread in Saudi Arabia, with no efficient treatment or prevention available as of yet. Although the rational drug design traditionally uses information on known 3D structures of viral proteins, intrinsically disordered proteins (i.e., functional proteins that do not possess unique 3D structures), with their multitude of disorder-dependent functions, are crucial for the biology of viruses. Here, viruses utilize disordered regions in their invasion of the host organisms and in hijacking and repurposing of different host systems. Furthermore, the ability of viruses to efficiently adjust and accommodate to their hostile habitats is also intrinsic disorderdependent. However, little is currently known on the level of penetrance and functional utilization of intrinsic disorder in the ALKV proteome. To fill this gap, we used here multiple computational tools to evaluate the abundance of intrinsic disorder in the ALKV genome polyprotein. We also analyzed the peculiarities of intrinsic disorder predisposition of the individual viral proteins, as well as human proteins known to be engaged in interaction with the ALKV proteins. Special attention was paid to finding a correlation between protein functionality and structural disorder. To the best of our knowledge, this work represents the first systematic study of the intrinsic disorder status of ALKV proteome and interactome.Electronic supplementary material The online version of this article (https ://doi.

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“…While the exact mechanism of PD pathogenesis is not completely understood, aggregation of the presynaptic protein α-synuclein (αS) is believed to play a crucial role in the etiology of this malady [ 1 , 2 , 3 ]. Being a typical intrinsically disordered protein, αS does not have a single biological function but possesses a multitude of functional activities [ 4 , 5 , 6 , 7 , 8 ]. For example, a significant fraction of αS is involved in interaction with membrane, especially synaptic vesicles associated with the vesicular transport processes.…”

Section: Introductionmentioning

confidence: 99%

“…Monomers and oligomers of αS and Aβ are the most critical players in the pathology of PD and AD, respectively and larger aggregate and fibril production are toxic as well, however, there is currently limited information about their formation rates in the patient brain (see [ 8 , 84 , 139 , 140 , 141 , 142 ] and references therein). Experimental and computational studies showed that these disordered proteins self-assemble into fibrils by a nucleation–condensation polymerization mechanism [ 143 , 144 , 145 ].…”

Section: Introductionmentioning

confidence: 99%

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

Coskuner‐Weber

Uversky

2018

IJMS

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Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies.

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Looking at the recent advances in understanding α-synuclein and its aggregation through the proteoform prism

Cited by 48 publications

References 200 publications

The effect of truncation on prion-like properties of α-synuclein

The effect of truncation on prion-like properties of α-synuclein

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

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