Parkinson’s disease (PD) is marked by different kinds of pathological features, one hallmark is the aggregation of α-synuclein (aSyn). The development of aSyn pathology in the substantia nigra is associated to the manifestation of motor deficits at the time of diagnosis. However, most of the patients suffer additionally from non-motor symptoms, which may occur already in the prodromal phase of the disease years before PD is diagnosed. Many of these symptoms manifest in the gastrointestinal system (GIT) and some data suggest a potential link to the occurrence of pathological aSyn forms within the GIT. These clinical and pathological findings lead to the idea of a gut-brain route of aSyn pathology in PD. The identification of pathological aSyn in the intestinal system, e.g., by GIT biopsies, is therefore of highest interest for early diagnosis and early intervention in the phase of formation and propagation of aSyn. However, reliable methods to discriminate between physiological and pathological forms of enteral aSyn on the cellular and biochemical level are still missing. Moreover, a better understanding of the physiological function of aSyn within the GIT as well as its structure and pathological aggregation pathways are crucial to understand its role within the enteric nervous system and its spreading from the gut to the brain. In this review, we summarize clinical manifestations of PD in the GIT, and discuss biochemical findings from enteral biopsies. The relevance of pathological aSyn forms, their connection to the gut-brain axis and new developments to identify pathologic forms of aSyn by structural features are critically reviewed.

Introduction: The polyphenolic spice and food coloring ingredient curcumin has beneficial effects in a broad variety of inflammatory diseases. Amongst them, curcumin has been shown to attenuate microglia reaction and prevent from glial scar formation in spinal cord and brain injuries. Methods: We developed a protocol for the efficient encapsulation of curcumin as a model for anti-inflammatory drugs yielding long-term stable, non-toxic liposomes with favorable physicochemical properties. Subsequently, we evaluate the effects of liposomal curcumin in experimental models for neuroinflammation and reactive astrogliosis. Results: We could show that liposomal curcumin can efficiently reduce the reactivity of human microglia and astrocytes and preserve tissue integrity of murine organotypic cortex slices. Discussion and Perspective: In perspective, we want to administer this curcumin formulation in brain implant coatings to prevent neuroinflammation and glial scar formation as foreign body responses of the brain towards implanted materials.

SARS-CoV-2, the virus causing the COVID-19 pandemic, changes frequently through the appearance of mutations constantly leading to new variants. However, only few variants evolve as dominating and will be considered as “Variants of Concern” (VOCs) by the world health organization (WHO). At the end of 2020 the alpha (B.1.1.7) variant appeared in the United Kingdom and dominated the pandemic situation until mid of 2021 when it was substituted by the delta variant (B.1.617.2) that first appeared in India as predominant. At the end of 2021, SARS-CoV-2 omicron (B.1.1.529) evolved as the dominating variant. Here, we use in silico modeling and molecular dynamics (MD) simulations of the receptor-binding domain of the viral spike protein and the host cell surface receptor ACE2 to analyze and compare the interaction pattern between the wild type, delta and omicron variants. We identified residue 493 in delta (glutamine) and omicron (arginine) with altered binding properties towards ACE2.

Virus-like-particles (VLPs) are attractive nanoparticulate scaffolds for broad applications in material/biological sciences and medicine. Prior their functionalization, specific adaptations have to be carried out. These adjustments frequently lead to disordered particles, but the particle integrity is an essential factor for the VLP suitability. Therefore, major requirements for particle stabilization exist. The objective of this study was to evaluate novel stabilizing elements for functionalized chimeric hepatitis B virus core antigen virus-like particles (HBcAg-VLP), with beneficial characteristics for vaccine development, imaging or delivery. The effects of a carboxy-terminal polyhistidine-peptide and an intradimer disulfide-bridge on the stability of preclinically approved chimeric HBcAg-VLPs were assessed. We purified recombinant chimeric HBcAg-VLPs bearing different modified C-termini and compared their physical and chemical particle stability by quantitative protein-biochemical and biophysical techniques. We observed lower chemical resistance of T = 3- compared to T = 4-VLP (triangulation number) capsids and profound impairment of accessibility of hexahistidine-peptides in assembled VLPs. Histidines attached to the C-terminus were associated with superior mechanical and/or chemical particle stability depending on the number of histidine moieties. A molecular modeling approach based on cryo-electron microscopy and biolayer interferometry revealed the underlying structural mechanism for the strengthening of the integrity of VLPs. Interactions triggering capsid stabilization occur on a highly conserved residue on the basis of HBcAg-monomers as well as on hexahistidine-peptides of adjacent monomers. This new stabilization mechanism appears to mimic an evolutionary conserved stabilization concept for hepadnavirus core proteins. These findings establish the genetically simply transferable C-terminal polyhistidine-peptide as a general stabilizing element for chimeric HBcAg-VLPs to increase their suitability.

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.

Lysosomes are specialized organelles with an acidic pH that act as recycling hubs for intracellular and extracellular components. They harbour numerous different hydrolytic enzymes to degrade substrates like proteins, peptides, and glycolipids. Reduced catalytic activity of lysosomal enzymes can cause the accumulation of these substrates and loss of lysosomal integrity, resulting in lysosomal dysfunction and lysosomal storage disorders (LSDs). Post-mitotic cells, such as neurons, seem to be highly sensitive to damages induced by lysosomal dysfunction, thus LSDs often manifest with neurological symptoms. Interestingly, some LSDs and Parkinson's disease (PD) share common cellular pathomechanisms, suggesting convergence of aetiology of the two disease types. This is further underlined by genetic associations of several lysosomal genes involved in LSDs with PD. The increasing number of lysosome-associated genetic risk factors for PD makes it necessary to understand functions and interactions of lysosomal proteins/enzymes both in health and disease, thereby holding the potential to identify new therapeutic targets. In this review, we highlight genetic and mechanistic interactions between the complex lysosomal network, LSDs and PD, and elaborate on methodical challenges in lysosomal research.