The Cellular Environment Affects Monomeric α-Synuclein Structure

Stephens, Amberley D.; Zacharopoulou, Maria; Schierle, Gabriele S. Kaminski

doi:10.1016/j.tibs.2018.11.005

Cited by 70 publications

(87 citation statements)

References 118 publications

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“…Therefore, the word 'monomer' actually describes a plethora of conformational states which are constantly reconfiguring. These dynamic interactions are heavily influenced by the surrounding environment of aSyn and their disruption can lead to skewing of the ensemble of monomeric conformations 6 . This, in turn, may influence which aggregation competent/ incompetent pathways are taken and whether these are subsequently toxic or not.…”

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confidence: 99%

Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

et al. 2020

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As an intrinsically disordered protein, monomeric alpha-synuclein (aSyn) occupies a large conformational space. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. We observe that the more exposed the N-terminus and the beginning of the NAC region of aSyn are, the more aggregation prone monomeric aSyn conformations become. Solvent exposure of the Nterminus of aSyn occurs upon release of C-terminus interactions when calcium binds, but the level of exposure and aSyn's aggregation propensity is sequence and post translational modification dependent. Identifying aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein.

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Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

et al. 2020

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“…[52] This aberrant protein behavior is known to play an important role in many diseases such as neurodegenerative pathologies.For instance,the brains of patients suffering from Parkinsonsd isease often exhibit large aggregates called Lewy bodies,w hich, at their core,c onsist of aggregated asynuclein proteins. [53] Therefore,b eing able to detect the misfolded state of such proteins at the early stage of the aggregation process can be of great importance for health applications including early diagnosis,u nderstanding of pathologies,and development of pharmaceutical drugs. [54] To track the conformational state of proteins in situ, it is essential to implement an integrated optofluidic device that combines the sensor metasurfaces with microfluidic channels to enable in-flow measurements.I ns uch devices,t he influence of strong water absorption bands on the sensor signal can be reduced significantly by reversing the CaF 2 substrate supporting the metasurface,allowing the incident IR light to pass through the transparent substrate instead of the water…”

Section: Minireviewsmentioning

confidence: 99%

Metasurface‐Based Molecular Biosensing Aided by Artificial Intelligence

et al. 2019

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Molecular spectroscopy provides unique information on the internal structure of biological materials by detecting the characteristic vibrational signatures of their constituent chemical bonds at infrared frequencies. Nanophotonic antennas and metasurfaces have driven this concept towards few‐molecule sensitivity by confining incident light into intense hot spots of the electromagnetic fields, providing strongly enhanced light‐matter interaction. In this Minireview, recently developed molecular biosensing approaches based on the combination of dielectric metasurfaces and imaging detection are highlighted in comparison to traditional plasmonic geometries, and the unique potential of artificial intelligence techniques for nanophotonic sensor design and data analysis is emphasized. Because of their spectrometer‐less operation principle, such imaging‐based approaches hold great promise for miniaturized biosensors in practical point‐of‐care or field‐deployable applications.

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“…[52] Dieses abnorme Proteinverhalten spielt gerade im Bereich der neurodegenerativen Krankheiten eine wichtige Rolle.B eispielsweise findet man in den Gehirnen von Parkinson-Patienten häufig sogenannte Lewy-Kçrperchen, welche im Kern aus aggregierten a-Synuclein-Proteinmolekülen bestehen. [53] Ausd iesem Grund ist die Erkennung von Protein-Fehlfaltungen fürm edizinische Anwendungen sehr wichtig,von der frühen Diagnose über eine bessere Kontrolle des Krankheitsfortschritts bis hin zur Entwicklung angepasster Therapieansätze. [54] Um die Faltungszustände von Proteinen in situ verfolgen zu kçnnen, ist ein optofluidischer Ansatz entscheidend, bei dem der metaoberflächenbasierte Sensor mit einer speziellen mikrofluidischen Durchflusszelle kombiniert wird.…”

Section: Plasmonische Antennen Fürdie Oberflächenverstärkte Spektroskunclassified

Metaoberflächen‐basierte molekulare Biosensorik unterstützt von künstlicher Intelligenz

et al. 2019

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Techniken der molekularen Absorptionsspektroskopie liefern einzigartige Informationen über die innere Zusammensetzung biologischer Materie, indem sie die charakteristischen Infrarot‐Vibrationsbanden der beteiligten Moleküle detektieren. Durch den Einsatz von nanophotonischen Antennen und Metaoberflächen lässt sich einfallendes Licht auf der Nanoskala bündeln, was zu starker Licht‐Materie‐Wechselwirkung führt und es erlaubt, dieses Sensorkonzept bis hin zur Detektion weniger Moleküle auszudehnen. In diesem Kurzaufsatz werden wir neuartige Metaoberflächen‐basierte Ansätze der molekularen Biosensorik vorstellen und mit traditionellen Konzepten vergleichen. Ein besonderes Augenmerk liegt auf der kürzlich eingeführten Kombination von dielektrischen Metaoberflächen mit bildgebender Detektion, sowie auf dem Potential von künstlicher Intelligenz für das Design nanophotonischer Sensoren und die Datenanalyse. Solche Methoden erlauben die Messung molekularer Signaturen ohne Verwendung klassischer IR‐Spektrometer oder durchstimmbarer Laserquellen und stellen somit einen Durchbruch für miniaturisierte Sensoren in der Umweltanalytik und der patientennahen Labordiagnostik dar.

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The Cellular Environment Affects Monomeric α-Synuclein Structure

Cited by 70 publications

References 118 publications

Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

Metasurface‐Based Molecular Biosensing Aided by Artificial Intelligence

Metaoberflächen‐basierte molekulare Biosensorik unterstützt von künstlicher Intelligenz

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