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Alpha-synuclein (α-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of α-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of α-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the gene, which encodes α-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the α-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of α-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on α-Syn have been generated. In this review, we summarize the main features of the α-Syn pre-formed fibrils (PFFs) model and recombinant adeno-associated virus vector (rAAV) mediated α-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Here, we show that injection of α-Syn PFFs and overexpression of α-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, α-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the α-Syn pathology. In contrast, rAAV-mediated α-Syn overexpression in the brain limits the α-Syn aggregates within the transduced neurons. Second, phosphorylated α-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas α-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated α-Syn reminiscent of Lewy bodies and Lewy neurites.

Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) are neurodegenerative disorders with alpha‐synuclein (α‐syn) aggregation pathology. Different strains of α‐syn with unique properties are suggested to cause distinct clinical and pathological manifestations resulting in PD, MSA, or DLB. To study individual α‐syn spreading patterns, we injected α‐syn fibrils amplified from brain homogenates of two MSA patients and two PD patients into the brains of C57BI6/J mice. Antibody staining against pS129‐α‐syn showed that α‐syn fibrils amplified from the brain homogenates of the four different patients caused different levels of α‐syn spreading. The strongest α‐syn pathology was triggered by α‐syn fibrils of one of the two MSA patients, followed by comparable pS129‐α‐syn induction by the second MSA and one PD patient material. Histological analysis using an antibody against Iba1 further showed that the formation of pS129‐α‐syn is associated with increased microglia activation. In contrast, no differences in dopaminergic neuron numbers or co‐localization of α‐syn in oligodendrocytes were observed between the different groups. Our data support the spreading of α‐syn pathology in MSA, while at the same time pointing to spreading heterogeneity between different patients potentially driven by individual patient immanent factors. Injection of alpha‐synuclein (α‐syn) fibrils amplified from brain homogenates of two multiple system atrophy patients and two Parkinson's disease patients into the brains of C57Bl6/J mice cause different levels of α‐syn spreading.

Scaffolds for tissue engineering application may be made from a collagenous extracellular matrix (ECM) of connective tissues because the ECM can mimic the functions of the target tissue. The primary sources of collagenous ECM material are calf skin and bone. However, these sources are associated with the risk of having bovine spongiform encephalopathy or transmissible spongiform encephalopathy. Alternative sources for collagenous ECM materials may be derived from livestock, e.g., pigs, and from marine animals, e.g., sea urchins. Collagenous ECM of the sea urchin possesses structural features and mechanical properties that are similar to those of mammalian ones. However, even more intriguing is that some tissues such as the ligamentous catch apparatus can exhibit mutability, namely rapid reversible changes in the tissue mechanical properties. These tissues are known as mutable collagenous tissues (MCTs). The mutability of these tissues has been the subject of on-going investigations, covering the biochemistry, structural biology and mechanical properties of the collagenous components. Recent studies point to a nerve-control system for regulating the ECM macromolecules that are involved in the sliding action of collagen fibrils in the MCT. This review discusses the key attributes of the structure and function of the ECM of the sea urchin ligaments that are related to the fibril-fibril sliding action—the focus is on the respective components within the hierarchical architecture of the tissue. In this context, structure refers to size, shape and separation distance of the ECM components while function is associated with mechanical properties e.g., strength and stiffness. For simplicity, the components that address the different length scale from the largest to the smallest are as follows: collagen fibres, collagen fibrils, interfibrillar matrix and collagen molecules. Application of recent theories of stress transfer and fracture mechanisms in fibre reinforced composites to a wide variety of collagen reinforcing (non-mutable) connective tissue, has allowed us to draw general conclusions concerning the mechanical response of the MCT at specific mechanical states, namely the stiff and complaint states. The intent of this review is to provide the latest insights, as well as identify technical challenges and opportunities, that may be useful for developing methods for effective mechanical support when adapting decellularised connective tissues from the sea urchin for tissue engineering or for the design of a synthetic analogue.

Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

The nanoscale fibrillar morphology, featuring long-range structural order, provides abundant interfaces for efficient exciton dissociation and high-quality pathways for effective charge transport, is a promising morphology for high performance organic solar cells. Here, we synthesize a thiophene terminated non-fullerene acceptor, L8-ThCl, to induce the fibrillization of both polymer donor and host acceptor, that surpasses the 20% efficiency milestone of organic solar cells. After adding L8-ThCl, the original weak and less continuous nanofibrils of polymer donors, i.e. PM6 or D18, are well enlarged and refined, whilst the host acceptor L8-BO also assembles into nanofibrils with enhanced structural order. By adapting the layer-by-layer deposition method, the enhanced structural order can be retained to significantly boost the power conversion efficiency, with specific values of 19.4% and 20.1% for the PM6:L8-ThCl/L8-BO:L8-ThCl and D18:L8-ThCl/L8-BO:L8-ThCl devices, with the latter being certified 20.0%, which is the highest certified efficiency reported so far for single-junction organic solar cells. The nanoscale fibrillar morphology of the photoactive layer is critical to improve performance of organic solar cells. Here, the authors incorporate thiophene terminal groups in the non-fullerene acceptor, realizing nanofibrils with enhanced structural order and certified device efficiency of 20%.

Atomic force microscopy (AFM) imaging enables the visualization of protein molecules with high resolution, providing insights into their shape, size, and surface topography. Here, we use AFM to study the aggregation process of protein S100A9 in physiological conditions, in the presence of calcium at a molar ratio 4Ca2+:S100A9. We find that S100A9 readily assembles into a worm-like fibril, with a period dimension along the fibril axis of 11.5 nm. The fibril’s chain length extends up to 136 periods after an incubation time of 144 h. At room temperature, the fibril’s bending stiffness was found to be 2.95×10−28 Nm2, indicating that the fibrils are relatively flexible. Additionally, the values obtained for the Young’s modulus (Ex=6.96×105 Pa and Ey=3.37×105 Pa) are four orders of magnitude lower than those typically reported for canonical amyloid fibrils. Our findings suggest that, under the investigated conditions, a distinct aggregation mechanism may be in place in the presence of calcium. Therefore, the findings reported here could have implications for the field of biomedicine, particularly with regard to Alzheimer’s disease.

Amyloid fibrils have evolved from purely pathological materials implicated in neurodegenerative diseases to efficient templates for last-generation functional materials and nanotechnologies. Due to their high intrinsic stiffness and extreme aspect ratio, amyloid fibril hydrogels can serve as ideal building blocks for material design and synthesis. Yet, in these gels, stiffness is generally not paired by toughness, and their fragile nature hinders significantly their widespread application. Here we introduce an amyloid-assisted biosilicification process, which leads to the formation of silicified nanofibrils (fibril–silica core–shell nanofilaments) with stiffness up to and beyond ∼20 GPa, approaching the Young’s moduli of many metal alloys and inorganic materials. The silica shell endows the silicified fibrils with large bending rigidity, reflected in hydrogels with elasticity three orders of magnitude beyond conventional amyloid fibril hydrogels. A constitutive theoretical model is proposed that, despite its simplicity, quantitatively interprets the nonmonotonic dependence of the gel elasticity upon the filaments bundling promoted by shear stresses. The application of these hybrid silica–amyloid hydrogels is demonstrated on the fabrication of mechanically stable aerogels generated via sequential solvent exchange, supercritical CO₂ removal, and calcination of the amyloid core, leading to aerogels of specific surface area as high as 993 m²/g, among the highest values ever reported for aerogels. We finally show that the scope of amyloid hydrogels can be expanded considerably by generating double networks of amyloid and hydrophilic polymers, which combine excellent stiffness and toughness beyond those of each of the constitutive individual networks.

α-Synuclein aggregation is a critical molecular process that underpins the pathogenesis of Parkinson’s disease. Aggregates may originate at synaptic terminals as a consequence of aberrant interactions between α-synuclein and lipids or evasion of proteostatic defences. The nature of these interactions is likely to influence the emergence of conformers or strains that in turn could explain the clinical heterogeneity of Parkinson’s disease and related α-synucleinopathies. For neurodegeneration to occur, α-synuclein assemblies need to exhibit seeding competency, i.e. ability to template further aggregation, and toxicity which is at least partly mediated by interference with synaptic vesicle or organelle homeostasis. Given the dynamic and reversible conformational plasticity of α-synuclein, it is possible that seeding competency and cellular toxicity are mediated by assemblies of different structure or size along this continuum. It is currently unknown which α-synuclein assemblies are the most relevant to the human condition but recent advances in the cryo-electron microscopic characterisation of brain-derived fibrils and their assessment in stem cell derived and animal models are likely to facilitate the development of precision therapies or biomarkers. This review summarises the main principles of α-synuclein aggregate initiation and propagation in model systems, and their relevance to clinical translation.