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Article ; Online: Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation.

Semerdzhiev, Slav A / Fakhree, Mohammad A A / Segers-Nolten, Ine / Blum, Christian / Claessens, Mireille M A E

ACS chemical neuroscience

2021 Volume 13, Issue 1, Page(s) 143–150

Abstract: First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson's disease (PD) have been reported. Currently, it is unclear if there is also a direct causal link between these diseases. To obtain first insights into ...

Abstract	First cases that point at a correlation between SARS-CoV-2 infections and the development of Parkinson's disease (PD) have been reported. Currently, it is unclear if there is also a direct causal link between these diseases. To obtain first insights into a possible molecular relation between viral infections and the aggregation of α-synuclein protein into amyloid fibrils characteristic for PD, we investigated the effect of the presence of SARS-CoV-2 proteins on α-synuclein aggregation. We show, in test tube experiments, that SARS-CoV-2 spike protein (S-protein) has no effect on α-synuclein aggregation, while SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds up the aggregation process. We observe the formation of multiprotein complexes and eventually amyloid fibrils. Microinjection of N-protein in SH-SY5Y cells disturbed the α-synuclein proteostasis and increased cell death. Our results point toward direct interactions between the N-protein of SARS-CoV-2 and α-synuclein as molecular basis for the observed correlation between SARS-CoV-2 infections and Parkinsonism.
MeSH term(s)	Amyloid/metabolism ; COVID-19 ; Coronavirus Nucleocapsid Proteins/metabolism ; Humans ; Phosphoproteins/metabolism ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; alpha-Synuclein/metabolism
Chemical Substances	Amyloid ; Coronavirus Nucleocapsid Proteins ; Phosphoproteins ; Spike Glycoprotein, Coronavirus ; alpha-Synuclein ; nucleocapsid phosphoprotein, SARS-CoV-2 ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.1c00666
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Article ; Online: Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein.

Lipiński, Wojciech P / Visser, Brent S / Robu, Irina / Fakhree, Mohammad A A / Lindhoud, Saskia / Claessens, Mireille M A E / Spruijt, Evan

Science advances

2022 Volume 8, Issue 48, Page(s) eabq6495

Abstract: Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role in the regulation of this process. While liquid-liquid phase separation of amyloidogenic proteins by themselves can act as an ... ...

Abstract	Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role in the regulation of this process. While liquid-liquid phase separation of amyloidogenic proteins by themselves can act as an alternative nucleation pathway, interaction of partly disordered aggregation-prone proteins with preexisting condensates that act as localization centers could be a far more general mechanism of altering their aggregation behavior. Here, we show that so-called host biomolecular condensates can both accelerate and slow down amyloid formation. We study the amyloidogenic protein α-synuclein and two truncated α-synuclein variants in the presence of three types of condensates composed of nonaggregating peptides, RNA, or ATP. Our results demonstrate that condensates can markedly speed up amyloid formation when proteins localize to their interface. However, condensates can also significantly suppress aggregation by sequestering and stabilizing amyloidogenic proteins, thereby providing living cells with a possible protection mechanism against amyloid formation.
Language	English
Publishing date	2022-12-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abq6495
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Article ; Online: Shaping membranes with disordered proteins.

Fakhree, Mohammad A A / Blum, Christian / Claessens, Mireille M A E

Archives of biochemistry and biophysics

2019 Volume 677, Page(s) 108163

Abstract: Membrane proteins control and shape membrane trafficking processes. The role of protein structure in shaping cellular membranes is well established. However, a significant fraction of membrane proteins is disordered or contains long disordered regions. ... ...

Abstract	Membrane proteins control and shape membrane trafficking processes. The role of protein structure in shaping cellular membranes is well established. However, a significant fraction of membrane proteins is disordered or contains long disordered regions. It becomes more and more clear that these disordered regions contribute to the function of membrane proteins. While the fold of a structured protein is essential for its function, being disordered seems to be a crucial feature of membrane bound intrinsically disordered proteins and protein regions. Here we outline the motifs that encode function in disordered proteins and discuss how these functional motifs enable disordered proteins to modulate membrane properties. These changes in membrane properties facilitate and regulate membrane trafficking processes which are highly abundant in eukaryotes.
MeSH term(s)	Amino Acid Motifs ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Humans ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/metabolism ; Membrane Lipids/metabolism ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Phase Transition ; Protein Domains
Chemical Substances	Intrinsically Disordered Proteins ; Membrane Lipids ; Membrane Proteins
Language	English
Publishing date	2019-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2019.108163
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Article ; Online: Exploring Intra- and Inter-Regional Interactions in the IDP α-Synuclein Using smFRET and MD Simulations.

Heesink, Gobert / Marseille, Mirjam J / Fakhree, Mohammad A A / Driver, Mark D / van Leijenhorst-Groener, Kirsten A / Onck, Patrick R / Blum, Christian / Claessens, Mireille M A E

Biomacromolecules

2023 Volume 24, Issue 8, Page(s) 3680–3688

Abstract: Theoretical concepts from polymer physics are often used to describe intrinsically disordered proteins (IDPs). However, amino acid interactions within and between regions of the protein can lead to deviations from typical polymer scaling behavior and ... ...

Abstract	Theoretical concepts from polymer physics are often used to describe intrinsically disordered proteins (IDPs). However, amino acid interactions within and between regions of the protein can lead to deviations from typical polymer scaling behavior and even to short-lived secondary structures. To investigate the key interactions in the dynamic IDP α-synuclein (αS) at the amino acid level, we conducted single-molecule fluorescence resonance energy transfer (smFRET) experiments and coarse-grained molecular dynamics (CG-MD) simulations. We find excellent agreement between experiments and simulations. Our results show that a physiological salt solution is a good solvent for αS and that the protein is highly dynamic throughout its entire chain, with local intra- and inter-regional interactions leading to deviations from global scaling. Specifically, we observe expansion in the C-terminal region, compaction in the NAC region, and a slightly smaller distance between the C- and N-termini than expected. Our simulations indicate that the compaction in the NAC region results from hydrophobic aliphatic contacts, mostly between valine and alanine residues, and cation-π interactions between lysine and tyrosine. In addition, hydrogen bonds also seem to contribute to the compaction of the NAC region. The expansion of the C-terminal region is due to intraregional electrostatic repulsion and increased chain stiffness from several prolines. Overall, our study demonstrates the effectiveness of combining smFRET experiments with CG-MD simulations to investigate the key interactions in highly dynamic IDPs at the amino acid level.
MeSH term(s)	alpha-Synuclein/chemistry ; Fluorescence Resonance Energy Transfer ; Molecular Dynamics Simulation ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/metabolism ; Amino Acids ; Protein Conformation
Chemical Substances	alpha-Synuclein ; Intrinsically Disordered Proteins ; Amino Acids
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1526-4602
ISSN (online)	1526-4602
DOI	10.1021/acs.biomac.3c00404
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Article: Shaping membranes with disordered proteins

Fakhree, Mohammad A.A / Blum, Christian / Claessens, Mireille M.A.E

Archives of biochemistry and biophysics. 2019 Nov. 30, v. 677

2019

Abstract	Membrane proteins control and shape membrane trafficking processes. The role of protein structure in shaping cellular membranes is well established. However, a significant fraction of membrane proteins is disordered or contains long disordered regions. It becomes more and more clear that these disordered regions contribute to the function of membrane proteins. While the fold of a structured protein is essential for its function, being disordered seems to be a crucial feature of membrane bound intrinsically disordered proteins and protein regions. Here we outline the motifs that encode function in disordered proteins and discuss how these functional motifs enable disordered proteins to modulate membrane properties. These changes in membrane properties facilitate and regulate membrane trafficking processes which are highly abundant in eukaryotes.
Keywords	cell membranes ; eukaryotic cells ; membrane proteins ; physiological transport ; protein structure
Language	English
Dates of publication	2019-1130
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2019.108163
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Article ; Online: The Localization of Alpha-synuclein in the Endocytic Pathway.

Fakhree, Mohammad A A / Konings, Irene B M / Kole, Jeroen / Cambi, Alessandra / Blum, Christian / Claessens, Mireille M A E

Neuroscience

2021 Volume 457, Page(s) 186–195

Abstract: Alpha-synuclein (αS) is an intrinsically disordered protein (IDP) that is abundantly present in the brain and is associated with Parkinson's disease (PD). In spite of its abundance and its contribution to PD pathogenesis, the exact cellular function of ... ...

Abstract	Alpha-synuclein (αS) is an intrinsically disordered protein (IDP) that is abundantly present in the brain and is associated with Parkinson's disease (PD). In spite of its abundance and its contribution to PD pathogenesis, the exact cellular function of αS remains largely unknown. The ability of αS to remodel phospholipid model membranes combined with biochemical and cellular studies suggests that αS is involved in endocytosis. To unravel with which route(s) and stage(s) of the endocytic pathway αS is associated, we quantified the colocalization between αS and endocytic marker proteins in differentiated SH-SY5Y neuronal cells, using an object based colocalization analysis. Comparison with randomized data allowed us to discriminate between structural and coincidental colocalizations. A large fraction of the αS positive vesicles colocalizes with caveolin positive vesicles, a smaller fraction colocalizes with EEA1 and Rab7. We find no structural colocalization between αS and clathrin and Rab11 positive vesicles. We conclude that in a physiological context, αS is structurally associated with caveolin dependent membrane vesiculation and is found further along the endocytic pathway, in decreasing amounts, on early and late endosomes. Our results not only shed new light on the function of αS, they also provide a possible link between αS function and vesicle trafficking malfunction in PD.
MeSH term(s)	Clathrin ; Endocytosis ; Humans ; Neurons ; Parkinson Disease ; alpha-Synuclein
Chemical Substances	Clathrin ; alpha-Synuclein
Language	English
Publishing date	2021-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2021.01.017
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Article ; Online: Different Conformational Subensembles of the Intrinsically Disordered Protein α-Synuclein in Cells.

Fakhree, Mohammad A A / Nolten, Ine Segers / Blum, Christian / Claessens, Mireille M A E

The journal of physical chemistry letters

2018 Volume 9, Issue 6, Page(s) 1249–1253

Abstract: The intrinsically disordered protein α-synuclein (αS) is thought to play an important role in cellular membrane processes. Although in vitro experiments indicate that this initially disordered protein obtains structure upon membrane binding, NMR and EPR ... ...

Abstract	The intrinsically disordered protein α-synuclein (αS) is thought to play an important role in cellular membrane processes. Although in vitro experiments indicate that this initially disordered protein obtains structure upon membrane binding, NMR and EPR studies in cells could not single out any conformational subensemble. Here we microinjected small amounts of αS, labeled with a Förster resonance energy transfer (FRET) pair, into SH-SY5Y cells to investigate conformational changes upon membrane binding. Our FRET studies show a clear conformational difference between αS in the cytosol and when bound to small vesicles. The identification of these different conformational subensembles inside cells resolves the apparent contradiction between in vitro and in vivo experiments and shows that at least two different conformational subensembles of αS exist in cells. The existence of conformational subensembles supports the idea that αS can obtain different functions which can possibly be dynamically addressed with changing intracellular physicochemical conditions.
MeSH term(s)	Cell Line, Tumor ; Cell Membrane/metabolism ; Fluorescence Resonance Energy Transfer ; Humans ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/metabolism ; Protein Conformation ; alpha-Synuclein/chemistry ; alpha-Synuclein/metabolism
Chemical Substances	Intrinsically Disordered Proteins ; alpha-Synuclein
Language	English
Publishing date	2018-02-27
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/acs.jpclett.8b00092
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Article ; Online: Cooperation of Helix Insertion and Lateral Pressure to Remodel Membranes.

Fakhree, Mohammad A A / Engelbertink, Sjoerd A J / van Leijenhorst-Groener, Kirsten A / Blum, Christian / Claessens, Mireille M A E

Biomacromolecules

2019 Volume 20, Issue 3, Page(s) 1217–1223

Abstract: Nature has developed different protein mediated mechanisms to remodel cellular membranes. One of the proteins that is implicated in these processes is α-synuclein (αS). Here we investigate if besides αS's membrane bound amphipathic helix the disordered, ... ...

Abstract	Nature has developed different protein mediated mechanisms to remodel cellular membranes. One of the proteins that is implicated in these processes is α-synuclein (αS). Here we investigate if besides αS's membrane bound amphipathic helix the disordered, solvent exposed tail of the protein contributes to membrane reshaping. We produced αS variants with elongated or truncated disordered solvent exposed domains. We observe a transformation of opaque multi lamellar vesicle solutions into nonscattering solutions containing smaller structures upon addition of all αS variants. Experimental data combined with model calculations show that the cooperation of helix insertion and lateral pressure exerted by the disordered domain makes the full length protein decidedly more efficient in membrane remodeling than the truncated version. Using disordered domains may not only be cost-efficient, it may also add a new level of control over vesicle fusion/fission by expansion or compaction of the domain.
MeSH term(s)	Cell Membrane ; Membrane Proteins/chemistry ; Pressure ; Protein Binding ; Protein Domains ; alpha-Synuclein/chemistry
Chemical Substances	Membrane Proteins ; alpha-Synuclein
Language	English
Publishing date	2019-02-20
Publishing country	United States
Document type	Journal Article
ISSN	1526-4602
ISSN (online)	1526-4602
DOI	10.1021/acs.biomac.8b01606
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Article: Cooperation of Helix Insertion and Lateral Pressure to Remodel Membranes

Fakhree, Mohammad A. A / Engelbertink, Sjoerd A. J / van Leijenhorst-Groener, Kirsten A / Blum, Christian / Claessens, Mireille M. A. E

Biomacromolecules. 2019 Jan. 17, v. 20, no. 3

2019

Abstract: Nature has developed different protein mediated mechanisms to remodel cellular membranes. One of the proteins that is implicated in these processes is α-synuclein (αS). Here we investigate if besides αS’s membrane bound amphipathic helix the disordered, ... ...

Abstract	Nature has developed different protein mediated mechanisms to remodel cellular membranes. One of the proteins that is implicated in these processes is α-synuclein (αS). Here we investigate if besides αS’s membrane bound amphipathic helix the disordered, solvent exposed tail of the protein contributes to membrane reshaping. We produced αS variants with elongated or truncated disordered solvent exposed domains. We observe a transformation of opaque multi lamellar vesicle solutions into nonscattering solutions containing smaller structures upon addition of all αS variants. Experimental data combined with model calculations show that the cooperation of helix insertion and lateral pressure exerted by the disordered domain makes the full length protein decidedly more efficient in membrane remodeling than the truncated version. Using disordered domains may not only be cost-efficient, it may also add a new level of control over vesicle fusion/fission by expansion or compaction of the domain.
Keywords	cell membranes ; cost effectiveness ; models ; proteins ; solvents ; surfactants
Language	English
Dates of publication	2019-0117
Size	p. 1217-1223.
Publishing place	American Chemical Society
Document type	Article
ISSN	1526-4602
DOI	10.1021/acs.biomac.8b01606
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Article ; Online: Review of pharmaceutical applications of N-methyl-2-pyrrolidone.

Jouyban, Abolghasem / Fakhree, Mohammad A A / Shayanfar, Ali

Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques

2011 Volume 13, Issue 4, Page(s) 524–535

Abstract: N-Methyl-2-pyrrolidone (NMP) or Pharmasolve is very strong solubilizing agent and it has important applications in different fields of industry. This review presents NMP physicochemical characteristics, application especially in pharmaceutical sciences, ... ...

Abstract	N-Methyl-2-pyrrolidone (NMP) or Pharmasolve is very strong solubilizing agent and it has important applications in different fields of industry. This review presents NMP physicochemical characteristics, application especially in pharmaceutical sciences, pharmacokinetic and toxicity. Characteristics of NMP such as physicochemical properties, solubilization efficacy, toxicity and adverse effects were compared with other common solvents used in the pharmaceutical industries. This review reveals that NMP is an acceptable pharmaceutical solvent and its efficacy, toxicity, and side effects are comparable with other common solvent.
MeSH term(s)	Animals ; Excipients/chemistry ; Excipients/pharmacokinetics ; Excipients/toxicity ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/chemistry ; Pyrrolidinones/chemistry ; Pyrrolidinones/pharmacokinetics ; Pyrrolidinones/toxicity ; Solubility ; Solvents/chemistry ; Solvents/pharmacokinetics ; Solvents/toxicity
Chemical Substances	Excipients ; Pharmaceutical Preparations ; Pyrrolidinones ; Solvents ; N-methylpyrrolidone (JR9CE63FPM)
Language	English
Publishing date	2011-04-11
Publishing country	Canada
Document type	Comparative Study ; Journal Article ; Review
ISSN	1482-1826
ISSN (online)	1482-1826
DOI	10.18433/j3p306
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