Publications by authors named "Daniel Erik Otzen"

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy.

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Many bacteria form biofilms to protect themselves from predators or stressful environmental conditions. In the biofilm, bacteria are embedded in a protective extracellular matrix composed of polysaccharides, proteins and extracellular DNA (eDNA). eDNA most often is released from lysed bacteria or host mammalian cells, and it is the only matrix component most biofilms appear to have in common.

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Parkinson's disease is a neurodegenerative movement disorder associated with the intracellular aggregation of α-synuclein (α-syn). Cytotoxicity is mainly associated with the oligomeric species (αSOs) formed at early stages in α-syn aggregation. Consequently, there is an intense focus on the discovery of novel inhibitors such as peptides to inhibit oligomer formation and toxicity.

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Oligomers of the protein α-synuclein (α-syn) are thought to be a major toxic species in Parkinson's disease, particularly through their ability to permeabilize cell membranes. The green tea polyphenol epigallocatechin gallate (EGCG) has been found to reduce this ability. We have analyzed α-syn oligomer dynamics and interconversion by H/D exchange monitored by mass spectrometry (HDX-MS).

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Protein coating material is important in many technological fields. The interaction between carbon nanomaterial and protein is especially interesting since it makes the development of novel hybrid materials possible. Functional bacterial amyloid (FuBA) is promising as a coating material because of its desirable features, such as well-defined molecular structure, robustness against harsh conditions, and easily engineerable functionality.

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Functional amyloid is produced by many organisms but is particularly well understood in bacteria, where proteins such as CsgA () and FapC () are assembled as functional bacterial amyloid (FuBA) on the cell surface in a carefully optimized process. Besides a host of helper proteins, FuBA formation is aided by multiple imperfect repeats which stabilize amyloid and streamline the aggregation mechanism to a fast-track assembly dominated by primary nucleation. These repeats, which are found in variable numbers in Pseudomonas, are most likely the structural core of the fibrils, though we still lack experimental data to determine whether the repeats give rise to β-helix structures via stacked β-hairpins (highly likely for CsgA) or more complicated arrangements (possibly the case for FapC).

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α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation.

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Article Synopsis
  • Dimethyl sulfoxide (DMSO) is a versatile solvent used in scientific research, known for its ability to dissolve both polar and nonpolar substances, as well as its role as a cryoprotectant in cell studies.
  • Recent findings indicate that even low concentrations of DMSO can disrupt key cellular processes and alter protein structures, particularly leading to the aggregation of α-synuclein, a protein linked to Parkinson's disease.
  • Experiments showed that DMSO promotes the formation of α-synuclein fibrils and enhances their aggregation in cells, which could influence research outcomes involving this protein, highlighting the need for caution when using DMSO in experiments.
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Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency.

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Article Synopsis
  • - The study investigates how lipid peroxidation products 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) affect the aggregation of α-synuclein (αSN), a protein linked to Parkinson's disease, showing that αSN oligomer stability and yield increase in the presence of these products.
  • - ONE is found to be more effective than HNE in inducing αSN aggregation, leading to differences in the size and shape of the resulting αSN oligomers (αSO), with ONE-αSO generally being smaller than HNE-αSO.
  • - The research highlights the significance of the His50 residue in αSN aggregation, showing that
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Functional amyloids are highly organized protein/peptide structures that promote biofilm formation in different bacteria. One such example is provided by a family of 20-45 residue-long peptides called phenol-soluble modulins (PSMs) from . External components such as eukaryotic host proteins, which alter self-assembly of bacterial amyloids, can affect the biofilm matrix.

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The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer.

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The anionic surfactant sodium dodecyl sulfate (SDS) interacts strongly with most globular proteins and denatures and unfolds them. While scattering studies using X-rays and neutrons have shown that this denaturation generally leads to protein-decorated SDS micelles, a different SDS-decorated polypeptide model has recently been suggested for complexes between SDS and Ubiquitin (UBI), in which individual SDS molecules are distributed on a partially stretched protein. To resolve this apparent discrepancy, we have investigated the SDS-UBI system by a number of complementary techniques.

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is a human pathogen that can cause chronic and recurrent infections and is recalcitrant to antibiotic chemotherapy. This trait is partly attributed to its ability to form persister cells, which are subpopulations of cells that are tolerant to lethal concentrations of antibiotics. Recently, we showed that the phenol-soluble modulins (PSMs) expressed by reduce persister cell formation.

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Bacterial functional amyloids are evolutionarily optimized to aggregate, so much so that the extreme robustness of functional amyloid makes it very difficult to examine their structure-function relationships in a detailed manner. Previous work has shown that functional amyloids are resistant to conventional chemical denaturants, but they dissolve in formic acid (FA) at high concentrations. However, systematic investigation requires a quantitative analysis of FA's ability to denature proteins.

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Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing.

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Protein fibrillation is traditionally associated with misfolding, loss of functional phenotype, and gain of toxicity in neurodegenerative diseases. However, many organisms exploit fibrils in the form of functional amyloids (FA), as seen in bacteria, such as E. coli, Salmonella, Bacillus, and Pseudomonas.

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Functional amyloid (FA) proteins have evolved to assemble into fibrils with a characteristic cross-β structure, which stabilizes biofilms and contributes to bacterial virulence. Some of the most studied bacterial FAs are the curli protein CsgA, expressed in a wide range of bacteria, and FapC, produced mainly by members of the genus. Though unrelated, both CsgA and FapC contain imperfect repeats believed to drive the formation of amyloid fibrils.

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Background: PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied.

Objectives: The purpose of this study was to investigate the PD-related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression.

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Parkinson's Disease (PD) is a neurodegenerative disease for which there currently is no cure. Aggregation of the pre-synaptic protein α-synuclein (aSN) into oligomers (αSOs) is believed to play a key role in PD pathology, but little is known about αSO formation in vivo and how they induce neurodegeneration. Both the naturally occurring polyunsaturated fatty acid docosahexaenoic acid (DHA) and the lipid peroxidation product 4-hydroxynonenal (HNE), strongly upregulated during ROS conditions, stimulate the formation of αSOs, highlighting a potential role in PD.

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The ability of proteins to aggregate to form well-organized β-sheet rich amyloid fibrils is increasingly viewed as a general if regrettable property of the polypeptide chain. Aggregation leads to diseases such as amyloidosis and neurodegeneration in humans and various mammalian species but is also found in a functional variety in both animals and microbes. However, there are to our knowledge no reports of amyloid formation in plants.

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Aggregation of the natively unfolded protein α-synuclein (α-syn) is key to the development of Parkinson's disease (PD). Some nanoparticles (NPs) can inhibit this process and in turn be used for treatment of PD. Using simulation strategies, we show here that α-syn self-assembly is electrostatically driven.

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The genera and contain species of anaerobic archaea that grow and divide within proteinaceous tubular sheaths that protect them from environmental stressors. The sheaths of PT are composed of the 60.9 kDa major sheath protein MspA.

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Does sodium dodecyl sulfate (SDS) denature proteins through electrostatic SDS-protein interactions? We show that a protein completely lacking charged side chains is unfolded by SDS in a manner similar to charged proteins, revealing that formal protein charges are not required for SDS-induced protein unfolding or binding.

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Liprotides are protein-lipid complexes in which the fatty acids form a micelle-like core surrounded by a shell of partially unfolded protein molecules. These complexes can be formed in different ways. The simplest approach is a thermal treatment where protein and fatty acid are mixed and then incubated at elevated temperatures.

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