Significance The deposition of α-synuclein as insoluble amyloid fibrils and the spreading such species in brain are two hallmarks Parkinson disease. It is therefore great importance to understand detail process aggregation this protein. We show by a series vitro measurements that can grow under wide range solution conditions but they multiply rapidly only much more select set conditions, mimicking those endosomes other organelles. quantitative characterization described here provides new...

Significance Parkinson’s disease is the second most prevalent neurodegenerative disorder and characterized by presence in brains of patients proteinaceous deposits whose main component α-synuclein. This protein interacts with membranes as part its biological function, but this interaction also modulates kinetics aggregation. Here, we show that, despite fact that α-synuclein binds to different types membranes, it only forms amyloid fibrils soluble lipids investigated here. finding particular...

Abstract Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Neurites containing α -synuclein fibrils. The underlying aggregation mechanism of this protein dominated a secondary process at mildly acidic pH, as in endosomes other organelles. This effect manifests strong acceleration the presence seeds weak dependence rate on monomer concentration. molecular could be nucleation monomers fibril surfaces or fragmentation. Here, we aim to distinguish...

Skin is attractive for drug therapy because it offers an easily accessible route without first-pass metabolism. Transdermal delivery also associated with high patient compliance and through the site of application, can be locally directed. However, to succeed transdermal often required overcome low permeability upper layer skin, stratum corneum (SC). One common strategy employ so-called penetration enhancers that supposedly act increase passage across SC. Still, there a lack understanding...

Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death the insulin-producing pancreatic beta-cells in patients Type 2 Diabetes Mellitus. A likely cause for cytotoxicity human IAPP that it destroys barrier properties membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles process hIAPP accompanied a loss function, whereby lipids are extracted from membrane and taken up forming deposits. No interaction was observed when preformed fibrils were...

Aggregated α-synuclein in Lewy bodies is one of the hallmarks Parkinson's disease (PD). Earlier observations aggregates neurons grafted into brains PD patients suggested cell-to-cell transfer and a prion-like me

Amyloid deposits from several human diseases have been found to contain membrane lipids. Co-aggregation of lipids and amyloid proteins in aggregates, the related extraction cellular membranes, can influence structure function both formed deposit. therefore important implications for pathological consequences formation. Still, very little is known about mechanism behind co-aggregation molecular aggregates. To address this, we study vitro by incubating phospholipid model membranes with...

Abstract Hydration is a key aspect of the skin that influences its physical and mechanical properties. Here, we investigate interplay between molecular macroscopic properties outer layer – stratum corneum (SC) how this varies with hydration. It shown hydration leads to changes in arrangement peptides keratin filaments as well dynamics C-H bond reorientation amino acids protruding terminals protein within SC. The structure occur at threshold corresponding ca. 85% relative humidity (RH)....

The upper layer of our skin, the stratum corneum (SC), is a versatile material that combines mechanical strength with efficient barrier function. In this paper, we discuss these macroscopic properties SC in relation to recent findings on molecular responses and structural diversity protein lipids. We put particular focus intermediate (colloidal) length scale how different substructures are organized respect each other, including effects non-equilibrium conditions skin gradients water other...

α-Synuclein is a small neuronal protein enriched at presynaptic termini. It hypothesized to play role in neurotransmitter release and synaptic vesicle cycling, while the formation of α-synuclein amyloid fibrils associated with several neurodegenerative diseases, most notably Parkinson's Disease. The molecular mechanisms both physiological pathological functions remain be fully understood, but cases, interactions membranes an important role. In this Perspective, we discuss aspects lipid...

Shear forces affect self-assembly processes ranging from crystallization to fiber formation. Here, the effect of mild agitation on amyloid fibril formation was explored for four peptides and investigated in detail A <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mrow> <mml:mi mathvariant="bold">β</mml:mi> </mml:mrow> </mml:math> 42, which is associated with Alzheimer’s disease. To gain mechanistic insights into agitation, nonseeded seeded...

Interactions between transmembrane helices play a key role in almost all cellular processes involving membrane proteins. We have investigated helix-helix interactions lipid bilayers with synthetic tryptophan-flanked peptides that mimic the spanning parts of The were functionalized pyrene to allow self-association be monitored by fluorescence and Trp-pyrene resonance energy transfer (FRET). Specific labeling at either their N or C terminus has shown association occurs exclusively antiparallel...

The natural moisturizing factor (NMF) is a group of hygroscopic molecules that naturally present in skin and protects from severe drying. Glycerol urea are two examples NMF components also used care applications. In the study, we investigate influence glycerol on permeability model drug (metronidazole, Mz) across excised pig membranes at different hydrating conditions. degree hydration regulated by gradient water activity membrane, which turn depends formulation contact with membrane. Here,...

Cardiolipin is a phospholipid found in the inner mitochondrial membrane and bacteria, it associated with many physiological functions. has dimeric structure consisting of two phosphatidyl residues connected by glycerol bridge four acyl chains, therefore can carry negative charges. The pKa values phosphate groups have previously been reported to differ widely pKa1 = 2.8 pKa2 7.5–9.5. Still, there are several examples experimental observations from cardiolipin-containing systems that do not...

An amyloid form of the protein α-synuclein is major component intraneuronal inclusions called Lewy bodies, which are neuropathological hallmark Parkinson's disease (PD). α-Synuclein known to associate with anionic lipid membranes, and interactions between aggregating cellular membranes thought be important for PD pathology. We have studied molecular determinants adsorption monomeric planar model composed zwitterionic phosphatidylcholine alone or in a mixture phosphatidylserine (relevant...

Despite the enormous potential for pharmaceutical applications, there is still a lack of understanding molecular details that can contribute to increased permeability stratum corneum (SC). To investigate influence hydration and heating on SC, we record natural-abundance 13C signal SC using polarization transfer solid-state NMR methods. Resonance lines from all major components are assigned. Comparison intensities obtained with INEPT CP pulse sequences gives information dynamics components....

In the development of transdermal and topical products it is important to understand how formulation ingredients interact with molecular components upper layer skin, stratum corneum (SC), thereby influence its macroscopic barrier properties. The aim here was investigate effect two commonly used excipients, transcutol dexpanthenol, on as well properties skin membrane. Polarization transfer solid-state NMR methods were combined steady-state flux impedance spectroscopy measurements these common...

The deposition of α-synuclein fibrils is one hallmark Parkinson's disease. Here, we investigate how ganglioside lipids, present in high amounts neurons and exosomes, influence the aggregation kinetics α-synuclein. Gangliosides, as well as, other anionic lipid species with small or large headgroups were found to induce conformational changes monomers catalyse their at mildly acidic conditions. Although extent this catalytic effect was slightly higher for gangliosides, results imply that...

The skin provides an attractive alternative to the conventional drug administration routes. Still, it comes with challenges as upper layer of skin, stratum corneum (SC), efficient barrier against permeation most compounds. One way overcome is apply chemical enhancers, which can modify SC structure. In this paper, we investigated molecular effect three different types glycols in SC: dipropylene glycol (diPG), propylene (PG), and butylene (BG). aim understand how these molecules influence...

The presence of amyloid fibrils is a hallmark several neurodegenerative diseases. Some amyloidogenic proteins, such as α-synuclein and β, interact with lipids, this interaction can strongly favour the formation fibrils. In particular primary nucleation step,