scholarly journals Structural basis of synaptic vesicle assembly promoted by α-synuclein

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Giuliana Fusco ◽  
Tillmann Pape ◽  
Amberley D. Stephens ◽  
Pierre Mahou ◽  
Ana Rita Costa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Familial Parkinson’S Disease

Abstractα-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor’ mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

scholarly journals Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein

2019 ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Simanta Sarani Paul ◽  
Pallabi Sil ◽  
Jayati Sengupta ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intrinsically Disordered Protein ◽  
Alpha Synuclein ◽  
Oligomeric State ◽  
Intrinsically Disordered ◽  
Nmr Study ◽  
Novel Strategy ◽  
Structural Architecture ◽  
Β Sheet

AbstractAggregation of the intrinsically disordered protein alpha-Synuclein (α-Syn) into insoluble fibrils with a cross-β sheet amyloid structure plays a key role in the neuronal pathology of Parkinson’s disease (PD). The fibrillation pathway of α-Syn encompasses a multitude of transient oligomeric forms differing in size, secondary structure, hydrophobic exposure and toxicity. According to a recent solid state NMR study, the fibrillating unit of α-Syn contains the core residues of the protein arranged into in-register parallel β sheets with a unique Greek key topology. Here, we have shown that the physiologically available small molecule heme (hemin chloride) when added at sub-stoichiometric ratios to either monomeric or aggregated α-Syn, arrests its aggregation in an oligomeric state, which is minimally toxic. Using cryo-EM, we observed that these heme-induced oligomers are ‘mace’-shaped and consist of approximately four monomers. However, the presence of a crucial twist or contortion in their Greek key structural architecture prevents further hierarchical appending into annular oligomers and protofilament formation. We confirm using a His50Gln mutant that the binding of heme onto His50 is crucial in inflicting the structural distortion and is responsible for the stabilization of the non-toxic and off-pathway α-Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far.

scholarly journals α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

2020 ◽  
Author(s):  
Schechter Meir ◽  
Atias Merav ◽  
Abd Elhadi Suaad ◽  
Davidi Dana ◽  
Gitler Daniel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Synaptic Vesicles ◽  
Causative Role ◽  
Coated Pits ◽  
Exact Role ◽  
Intrinsically Disordered

Abstractα-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we have investigated the role of α-Syn in membrane trafficking through its association with acidic phosphoinositides (PIPs), such as phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor AP2 at clathrin-coated pits. Using endocytosis of transferrin, an indicator of clathrin mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI4,5P2 levels. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by α-Syn mutations. In accord with their effects on PI4,5P2 levels at the plasma membrane, the PD associated E46K and A53T mutations further enhance SV endocytosis. However, neither A30P mutation, nor Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, that interfere with phospholipid binding, affect SV endocytosis. This study provides evidence for a critical involvement of PIPs in α-Syn-mediated membrane trafficking.Significance Statementα-Synuclein (α-Syn) protein is known for its causative role in Parkinson’s disease. α-Syn is normally involved in mechanisms of membrane trafficking, including endocytosis, exocytosis and synaptic vesicles cycling. However, a certain degree of controversy regarding the exact role of α-Syn in these mechanisms persists. Here we show that α-Syn acts to increase plasma membrane levels PI4,5P2 and PI3,4P2 to facilitate clathrin mediated and synaptic vesicles endocytosis. Based on the results, we suggest that α-Syn interactions with the acidic phosphoinositides facilitate a shift in their homeostasis to support endocytosis.

scholarly journals LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

2018 ◽  
Vol 17 (7) ◽  
pp. 597-608 ◽  
Author(s):  
Marialuisa Quadri ◽  
Wim Mandemakers ◽  
Martyna M Grochowska ◽  
Roy Masius ◽  
Hanneke Geut ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Genome Wide ◽  
A Genome ◽  
Familial Parkinson’S Disease

Does human alpha synuclein behave like prions?

2021 ◽  
Vol 20 ◽  
Author(s):  
Yasir Hasan Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Present Review ◽  
Exact Role

: Alpha synuclein (α-synuclein) is a protein which is abundantly found in brain and in lesser amount in heart and muscles. The exact role of α-synuclein is not known but it is consider to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies which specifically damage the dopaminergic neurons in the subtantianigra of the mid brain and leads to the progression of Parkinson’s disease (PD). There are evidences that aggregates of α-synuclein behaves like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

scholarly journals Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Michael X. Henderson ◽  
Medha Sengupta ◽  
John Q. Trojanowski ◽  
Virginia M. Y. Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Clinical Presentation ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Tau Pathology ◽  
Mutation Carriers ◽  
Familial Parkinson’S Disease

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). While the clinical presentation of LRRK2 mutation carriers is similar to that of idiopathic PD (iPD) patients, the neuropathology of LRRK2 PD is less clearly defined. Lewy bodies (LBs) composed of α-synuclein are a major feature of iPD, but are not present in all LRRK2 PD cases. There is some evidence that tau may act as a neuropathological substrate in LB-negative LRRK2 PD, but this has not been examined systematically. In the current study, we examined α-synuclein, tau, and amyloid β (Aβ) pathologies in 12 LRRK2 mutation carriers. We find that α-synuclein pathology is present in 63.6% of LRRK2 mutation carriers, but tau pathology can be found in 100% of carriers and is abundant in 91% of carriers. We further use an antibody which selectively binds Alzheimer’s disease (AD)-type tau and use quantitative analysis of tau pathology to demonstrate that AD tau is the prominent type of tau present in LRRK2 mutation carriers. Abundant Aβ pathology can also be found in LRRK2 mutation carriers and is consistent with comorbid AD pathology. Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2 PD shares clinical and pathological features of idiopathic PD. The prevalence of AD-type tau pathology in LRRK2 PD is an important consideration for understanding PD pathogenesis and refining clinical trial inclusion and progression criterion.

scholarly journals The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1192
Author(s):  
Line K. Skaanning ◽  
Angelo Santoro ◽  
Thomas Skamris ◽  
Jacob Hertz Martinsen ◽  
Anna Maria D’Ursi ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Structural Changes ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Molar Ratio ◽  
Type I ◽  
Dependent Manner ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Main Component

The intrinsically disordered protein α-synuclein (aSN) is, in its fibrillated state, the main component of Lewy bodies—hallmarks of Parkinson’s disease. Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of sulfation. Heparin, a highly sulfated glycosaminoglycan, is a relevant mimic for mature heparan sulfate and has been shown to influence aSN fibrillation. Here, we decompose the underlying properties of the interaction between heparin and aSN and the effect of heparin on fibrillation. Via the isolation of the first 61 residues of aSN, which lacked intrinsic fibrillation propensity, fibrillation could be induced by heparin, and access to the initial steps in fibrillation was possible. Here, structural changes with shifts from disorder via type I β-turns to β-sheets were revealed, correlating with an increase in the aSN1–61/heparin molar ratio. Fluorescence microscopy revealed that heparin and aSN1–61 co-exist in the final fibrils. We conclude that heparin can induce the fibrillation of aSN1–61, through binding to the N-terminal with an affinity that is higher in the truncated form of aSN. It does so by specifically modulating the structure of aSN via the formation of type I β-turn structures likely critical for triggering aSN fibrillation.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

Differences in glucose metabolism between dementia with Lewy bodies and dementia associated with Parkinson's disease

2005 ◽  
Vol 32 (S 4) ◽  
Author(s):  
P Häussermann ◽  
A.O Ceballos-Baumann ◽  
H Förstl ◽  
R Feurer ◽  
B Conrad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glucose Metabolism ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

2018 ◽  
Author(s):  
Sarah Klass ◽  
Matthew J. Smith ◽  
Tahoe Fiala ◽  
Jessica Lee ◽  
Anthony Omole ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fusion Proteins ◽  
Organic Molecules ◽  
Intrinsically Disordered Protein ◽  
Protein Domain ◽  
Enzymatic Cleavage ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Self Assembling ◽  
Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

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