Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Surguchov, Andrei; Surguchev, Alexei

doi:10.3390/biomedicines10123241

Cited by 34 publications

(28 citation statements)

References 98 publications

(162 reference statements)

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“…A model system has been established with SYN and TPPP, which are expressed endogenously in neurons and OLGs, respectively, in normal human brain (Figure 7) [34,[48][49][50]. The Coco program simulates certain related experimental phenomena, namely, the promotion of phenotype alterations by the transmission of SYN into OLGs or of TPPP into neuronal cells, which is due to the hetero-association of the disordered TPPP with another disordered protein, SYN [17,[51][52][53][54][55]. In addition, the pathological overexpression of SYN could be considered as acting as a second PPDP resulting in SYN assembly with phenotypic alteration as illustrated by the Coco program.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of TPPP, its stabilization of the microtubule network is central to differentiation; this stabilization is disrupted by the pathological presence of SYN. The hypothesis may therefore even prove helpful in understanding and treating diseases like Parkinson's disease and multiple system atrophy in which the interactions between SYN and TPPP are implicated [15][16][17]36,51].…”

Section: Discussionmentioning

confidence: 99%

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The Sherpa hypothesis: Phenotype-Protecting Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Norris

Oláh

Krylov

et al. 2023

Preprint

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Intrinsically disordered proteins (IDPs) are central to many physiological functions and to various pathologies that include neurodegeneration. They can interact with numerous partner proteins. Here, we introduce the Sherpa hypothesis, according to which a subset of stable IDPs, which we term Phenotype-Preserving Disordered Proteins (PPDP), play a central role in protecting cell phenotypes from perturbations. To illustrate and test this hypothesis, we computer-simulate some salient features of how cells evolve and differentiate in the presence of either a single PPDP or two incompatible PPDPs. We relate this virtual experiment to the pathological interactions between two PPDPs, α-synuclein and Tubulin Polymerization Promoting Protein/p25, in neurodegenerative disorders. Finally, we discuss the implications of the Sherpa hypothesis for aptamer-based therapies of such disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Sherpa hypothesis: Phenotype-Protecting Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Norris

Oláh

Krylov

et al. 2023

Preprint

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“…Another member of amyloidogenic PPs, α-synuclein [ 17 , 18 ], also directly interacts with SARS-CoV-2 proteins, i.e., the spike (S) and nucleocapsid (N) proteins [ 19 ]. Recent data show that the expression of α-synuclein is upregulated, and its aggregation is enhanced by viral S- and N-proteins.…”

Section: Pathogenic Properties Of Amyloidogenic Ppsmentioning

confidence: 99%

“…Numerous results point to the ability of α-synuclein, β-amyloid, and other amyloidogenic PPs to acquire toxic properties [ 1 , 2 , 3 , 4 , 17 , 44 ]. These findings have been so convincing that data about their antibacterial and antiviral activity has remained in the shadow for a long time.…”

Section: Antimicrobial and Antiviral Properties Of Amyloidogenic Ppsmentioning

confidence: 99%

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

et al. 2023

Self Cite

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For a long time, studies of amyloidogenic proteins and peptides (amyloidogenic PPs) have been focused basically on their harmful properties and association with diseases. A vast amount of research has investigated the structure of pathogenic amyloids forming fibrous deposits within or around cells and the mechanisms of their detrimental actions. Much less has been known about the physiologic functions and beneficial properties of amyloidogenic PPs. At the same time, amyloidogenic PPs have various useful properties. For example, they may render neurons resistant to viral infection and propagation and stimulate autophagy. We discuss here some of amyloidogenic PPs’ detrimental and beneficial properties using as examples beta-amyloid (β-amyloid), implicated in the pathogenesis of Alzheimer’s disease (AD), and α-synuclein—one of the hallmarks of Parkinson’s disease (PD). Recently amyloidogenic PPs’ antiviral and antimicrobial properties have attracted attention because of the COVID-19 pandemic and the growing threat of other viral and bacterial-induced diseases. Importantly, several COVID-19 viral proteins, e.g., spike, nucleocapsid, and envelope proteins, may become amyloidogenic after infection and combine their harmful action with the effect of endogenous APPs. A central area of current investigations is the study of the structural properties of amyloidogenic PPs, defining their beneficial and harmful properties, and identifying triggers that transform physiologically important amyloidogenic PPs into vicious substances. These directions are of paramount importance during the current SARS-CoV-2 global health crisis.

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“…The progression of neurodegenerative diseases such as Alzheimer’s [ 1 ] is mainly due to the loss of neuronal structure and function. Misfolding and abnormal aggregation of some proteins significantly contribute to their cause, including Tau-protein, Prion-protein, and α-synuclein (α-Syn) [ 2 ]. α-Syn is an intrinsically disordered protein of 140 amino acids that is expressed in the central nervous system at presynaptic and perinuclear sites [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs

Zhao

Zhang

et al. 2023

Biomolecules

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The aggregation of alpha-synuclein (α-Syn) is closely related to the occurrence of some neurodegenerative diseases such as Parkinson’s disease. The misfolding of α-Syn monomer plays a key role in the formation of aggregates and extension of fibril. However, the misfolding mechanism of α-Syn remains elusive. Here, three different α-Syn fibrils (isolated from a diseased human brain, generated by in vitro cofactor-tau induction, and obtained by in vitro cofactor-free induction) were selected for the study. The misfolding mechanisms of α-Syn were uncovered by studying the dissociation of the boundary chains based on the conventional molecular dynamics (MD) and Steered MD simulations. The results showed that the dissociation paths of the boundary chains in the three systems were different. According to the reverse process of dissociation, we concluded that in the human brain system, the binding of the monomer and template starts from the C-terminal and gradually misfolds toward the N-terminal. In the cofactor-tau system, the monomer binding starts from residues 58–66 (contain β3), followed by the C-terminal coil (residues 67–79). Then, the N-terminal coil (residues 36–41) and residues 50–57 (contain β2) bind to the template, followed by residues 42–49 (contain β1). In the cofactor-free system, two misfolding paths were found. One is that the monomer binds to the N/C-terminal (β1/β6) and then binds to the remaining residues. The other one is that the monomer binds sequentially from the C- to N-terminal, similar to the human brain system. Furthermore, in the human brain and cofactor-tau systems, electrostatic interactions (especially from residues 58–66) are the main driving force during the misfolding process, whereas in the cofactor-free system, the contributions of electrostatic and van der Waals interactions are comparable. These results may provide a deeper understanding for the misfolding and aggregation mechanism of α-Syn.

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Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

Cited by 34 publications

References 98 publications

The Sherpa hypothesis: Phenotype-Protecting Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

The Sherpa hypothesis: Phenotype-Protecting Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs

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