Is a cure for Parkinson's disease hiding inside us?

α-Synuclein (a-syn) oligomers and fibrils are behind neurodegeneration in Parkinson's disease (PD), but therapeutically targeting them is challenging. Amphipathic and cationic helical peptides inhibit amyloid formation and suppress neurotoxicity by selectively binding the solvent-accessible regions in these toxic species. Can endogenous peptides, like LL-37, constitute a new therapeutic paradigm in PD?

Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence.

Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation.

The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.

The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains.

Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation.

SolupHred: a server to predict the pH-dependent aggregation of intrinsically disordered proteins.

SUMMARY: Polypeptides are exposed to changing environmental conditions that modulate their intrinsic aggregation propensities. Intrinsically disordered proteins (IDPs) constitutively expose their aggregation determinants to the solvent, thus being especially sensitive to its fluctuations. However, solvent conditions are often disregarded in computational aggregation predictors. We recently developed a phenomenological model to predict IDPs' solubility as a function of the solution pH, which is based on the assumption that both protein lipophilicity and charge depend on this parameter. The model anticipated solubility changes in different IDPs accurately. In this application note, we present SolupHred, a web-based interface that implements the aforementioned theoretical framework into a predictive tool able to compute IDPs aggregation propensities as a function of pH. SolupHred is the first dedicated software for the prediction of pH-dependent protein aggregation. AVAILABILITY AND IMPLEMENTATION: The SolupHred web server is freely available for academic users at: https://ppmclab.pythonanywhere.com/SolupHred. It is platform-independent and does not require previous registration. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Insight into the specificity and severity of pathogenic mechanisms associated with missense mutations through experimental and structural perturbation analyses.

Most pathogenic missense mutations cause specific molecular phenotypes through protein destabilization. However, how protein destabilization is manifested as a given molecular phenotype is not well understood. We develop here a structural and energetic approach to describe mutational effects on specific traits such as function, regulation, stability, subcellular targeting or aggregation propensity. This approach is tested using large-scale experimental and structural perturbation analyses in over thirty mutations in three different proteins (cancer-associated NQO1, transthyretin related with amyloidosis and AGT linked to primary hyperoxaluria type I) and comprising five very common pathogenic mechanisms (loss-of-function and gain-of-toxic function aggregation, enzyme inactivation, protein mistargeting and accelerated degradation). Our results revealed that the magnitude of destabilizing effects and, particularly, their propagation through the structure to promote disease-associated conformational states largely determine the severity and molecular mechanisms of disease-associated missense mutations. Modulation of the structural perturbation at a mutated site is also shown to cause switches between different molecular phenotypes. When very common disease-associated missense mutations were investigated, we also found that they were not among the most deleterious possible missense mutations at those sites, and required additional contributions from codon bias and effects of CpG sites to explain their high frequency in patients. Our work sheds light on the molecular basis of pathogenic mechanisms and genotype-phenotype relationships, with implications for discriminating between pathogenic and neutral changes within human genome variability from whole genome sequencing studies.

Detection of the Faraday Chiral Anisotropy.

The connection between chirality and electromagnetism has attracted much attention through the recent history of science, allowing the discovery of crucial nonreciprocal optical phenomena within the context of fundamental interactions between matter and light. A major phenomenon within this family is the so-called Faraday chiral anisotropy, the long-predicted but yet unobserved effect which arises due to the correlated coaction of both natural and magnetically induced optical activities at concurring wavelengths in chiral systems. Here, we report on the detection of the elusive anisotropic Faraday chiral phenomenon and demonstrate its enantioselectivity. The existence of this fundamental effect reveals the accomplishment of envisioned nonreciprocal electromagnetic metamaterials referred to as Faraday chiral media, systems where novel electromagnetic phenomena such as negative refraction of light at tunable wavelengths or even negative reflection can be realized. From a more comprehensive perspective, our findings have profound implications for the general understanding of parity-violating photon-particle interactions in magnetized media.

Superior sagittal sinus-to-internal jugular vein bypass shunt with covered stent construct for intractable intracranial hypertension resulting from iatrogenic supratorcular sinus occlusion: technical note.

BACKGROUND: Acute occlusion of the posterior sagittal sinus may lead to dramatic increase in intracranial pressure (ICP), refractory to standard treatment. Hybrid vascular bypass of cranial venous outflow into the internal jugular vein (IJV) has seldom been described for this in recent neurosurgical literature. OBJECTIVE: To describe creation of a novel vascular bypass shunt from the superior sagittal sinus (SSS) to internal jugular vein (IJV) utilizing a covered stent-Dacron graft construct for control of refractory ICP. METHODS: We illustrate a patient with refractory ICP increases after acute sinus ligation that was performed to halt torrential bleeding from intraoperative injury. A temporary shunt was created that successfully controlled ICP. From the promising results of the temporary shunt, we utilized a prosthetic hybrid bypass graft to function as a shunt from the sagittal sinus to IJV. Yet the associated anticoagulation led to complications and a poor outcome. RESULTS: Rapid and sustained ICP reduction can be expected after sagittal sinus-to-jugular bypass shunt placement in acute sinus occlusion. Details of the surgical technique are described. Heparin anticoagulation, while imperative, is also associated with worrisome complications. CONCLUSION: Acute occlusion of posterior third of sagittal sinus carries a very malignant clinical course. Intractable intracranial hypertension from acute sinus occlusion may be effectively treated with a SSS-IJV bypass shunt. A covered stent construct provides an effective vascular bypass conduit. However, the anticoagulation risk can lead to fatal outcomes. The neurosurgeon must always strive for primary repair of an injured sinus.

In Vitro Effect of Dovitinib (TKI258), a Multi-Target Angiokinase Inhibitor on Aggressive Meningioma Cells.

Background: Meningiomas represent ∼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.

Safety Assessment of an A-Scan Ultrasonic System for Ophthalmic Use.

OBJECTIVES: This study describes the safety assessment of an A-scan ultrasonic system for ophthalmic use. The system is an investigational medical device for automatic cataract detection and classification. METHODS: The risk management was based on the International Organization for Standardization (ISO) standard DIN EN ISO 14971:2009-10 and International Electrotechnical Commission (IEC) standard IEC 60601-2-37. The calibration of the ultrasonic field was conducted according to the standards IEC 62127-1:2007 and IEC 62359:2010. The uncertainty on measurements was delineated in agreement with the guide JCGM 100:2008. RESULTS: After risk management, all risks were qualitatively classified as acceptable. The mechanical index (0.08 ± 0.05), soft tissue thermal index (0.08 ± 0.08) and spatial-peak temporal-average intensity (0.56 ± 0.59 mW/cm2 ) were under the maximum index values indicated by the US Food and Drug Administration guidance, Marketing Clearance of Diagnostic Ultrasound Systems and Transducers (0.23, 1, and 17 mW/cm2 , respectively). CONCLUSIONS: This study presents a practical approach for the safety assessment of A-scan ultrasonic systems for ophthalmic use. The safety evaluation of a medical device is mandatory before its use in clinical practice. However, the safety monitoring throughout its life cycle should also be considered, since many device components may deteriorate over time and use.

DispHred: A Server to Predict pH-Dependent Order-Disorder Transitions in Intrinsically Disordered Proteins.

The natively unfolded nature of intrinsically disordered proteins (IDPs) relies on several physicochemical principles, of which the balance between a low sequence hydrophobicity and a high net charge appears to be critical. Under this premise, it is well-known that disordered proteins populate a defined region of the charge-hydropathy (C-H) space and that a linear boundary condition is sufficient to distinguish between folded and disordered proteins, an approach widely applied for the prediction of protein disorder. Nevertheless, it is evident that the C-H relation of a protein is not unalterable but can be modulated by factors extrinsic to its sequence. Here, we applied a C-H-based analysis to develop a computational approach that evaluates sequence disorder as a function of pH, assuming that both protein net charge and hydrophobicity are dependent on pH solution. On that basis, we developed DispHred, the first pH-dependent predictor of protein disorder. Despite its simplicity, DispHred displays very high accuracy in identifying pH-induced order/disorder protein transitions. DispHred might be useful for diverse applications, from the analysis of conditionally disordered segments to the synthetic design of disorder tags for biotechnological applications. Importantly, since many disorder predictors use hydrophobicity as an input, the here developed framework can be implemented in other state-of-the-art algorithms.

Rathke's Cleft Cyst Apoplexy in Two Teenage Sisters.

Rathke's cleft cysts (RCC) are sellar-suprasellar cysts that are usually discovered incidentally given their indolent clinical course. When symptoms do arise, the most common clinical presentation is headache, visual field deficits due to visual pathway compression, diplopia due to cavernous sinus compression, chemical meningitis due to spillage of the cyst contents, endocrine dysfunction, and very rarely apoplexy. We present 2 cases of RCC in sisters who developed a sudden onset of symptoms in a manner similar to pituitary apoplexy. Interestingly, one of them had a very unusual presentation with seizure. We hypothesize that acute symptoms occur due to aggressive intracystic overproduction of mucopolysaccharides (with or without hemorrhage) and a resulting compressive syndrome or local irritation of surrounding structures by spillage of the cyst contents. RCC can be encountered incidentally in family members or may have a familiar predisposition. Since both sisters presented here developed apoplexy symptoms, we propose a more frequent follow-up with sequential imaging in patients with a family history of RCC. Transsphenoidal surgery with evacuation of the cyst contents is the treatment modality of choice, with excellent outcomes.

A Graphene-Edge Ferroelectric Molecular Switch.

We show that polar molecules (water, ammonia, and nitrogen dioxide) adsorbed solely at the exposed edges of an encapsulated graphene sheet exhibit ferroelectricity, collectively orienting and switching reproducibly between two available states in response to an external electric field. This ferroelectric molecular switching introduces drastic modifications to the graphene bulk conductivity and produces a large and ambipolar charge bistability in micrometer-size graphene devices. This system comprises an experimental realization of envisioned memory capacitive ("memcapacitive") devices whose capacitance is a function of their charging history, here conceived via confined and correlated polar molecules at the one-dimensional edge of a two-dimensional crystal.

The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region.

Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1) protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.

Animal model for in-vivo Nuclear Cataract. Lens hardness and elasticity assessment.

Age-related cataract is the most frequent cause of blindness in the world being responsible for 48% of blindness and affecting more than 10% of the working population. Currently there is no objective data of the lens biomechanical properties so the process by which the cataract affects the lens's properties (e.g. hardness and elasticity) is still unclear. A modified animal model was produced to create different severities of nuclear cataract. Different doses of sodium selenite were injected in two different moments of the rat' eyes maturation resulting in 12, 13 and 11 rats with incipient, moderate and severe cataract, respectively. The nucleus and cortex's hardness and the stiffness were measured using NanoTest™. Statistically significant differences were found between healthy and cataractous lenses. Statistically significant differences were also found between the different nuclear cataract degrees (p = 0.016), showing that the lens' hardness increases with cataract formation. The nucleus shows a higher hardness increase with cataract formation (p = 0.049). The animal model used in this study allowed for the first time the characterization of the lens's hardness and elasticity in two regions of the lens, in healthy and cataractous lenses.

An α-helical peptide-based plasmonic biosensor for highly specific detection of α-synuclein toxic oligomers.

BACKGROUND: α-Synuclein (αS) aggregation is the main neurological hallmark of a group of neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. αS oligomers are elevated in the cerebrospinal fluid (CSF) of PD patients, standing as a biomarker for disease diagnosis. However, methods for early PD detection are still lacking. We have recently identified the amphipathic 22-residue peptide PSMα3 as a high-affinity binder of αS toxic oligomers. PSMα3 displayed excellent selectivity and reproducibility, binding to αS toxic oligomers with affinities in the low nanomolar range and without detectable cross-reactivity with functional monomeric αS. RESULTS: In this work, we leveraged these PSMα3 unique properties to design a plasmonic-based biosensor for the direct detection of toxic oligomers under label-free conditions. SIGNIFICANCE AND NOVELTY: We describe the integration of the peptide in a lab-on-a-chip plasmonic platform suitable for point-of-care measurements of αS toxic oligomers in CSF samples in real-time and at an affordable cost, providing an innovative biosensor for PD early diagnosis in the clinic.

A new classification of parasagittal bridging veins based on their configurations and drainage routes pertinent to interhemispheric approaches: a surgical anatomical study.

OBJECTIVE: Opening the roof of the interhemispheric microsurgical corridor to access various neurooncological or neurovascular lesions can be demanding because of the multiple bridging veins that drain into the sinus with their highly variable, location-specific anatomy. The objective of this study was to propose a new classification system for these parasagittal bridging veins, which are herein described as being arranged in 3 configurations with 4 drainage routes. METHODS: Twenty adult cadaveric heads (40 hemispheres) were examined. From this examination, the authors describe 3 types of configurations of the parasagittal bridging veins relative to specific anatomical landmarks (coronal suture, postcentral sulcus) and their drainage routes into the superior sagittal sinus, convexity dura, lacunae, and falx. They also quantify the relative incidence and extension of these anatomical variations and provide several preoperative, postoperative, and microneurosurgical clinical case study examples. RESULTS: The authors describe 3 anatomical configurations for venous drainage, which improves on the 2 types that have been previously described. In type 1, a single vein joins; in type 2, 2 or more contiguous veins join; and in type 3, a venous complex joins at the same point. Anterior to the coronal suture, the most common configuration was type 1 dural drainage, occurring in 57% of hemispheres. Between the coronal suture and the postcentral sulcus, most veins (including 73% of superior anastomotic veins of Trolard) drain first into a venous lacuna, which are larger and more numerous in this region. Posterior to the postcentral sulcus, the most common drainage route was through the falx. CONCLUSIONS: The authors propose a systematic classification for the parasagittal venous network. Using anatomical landmarks, they define 3 venous configurations and 4 drainage routes. Analysis of these configurations with respect to surgical routes indicates 2 highly risky interhemispheric surgical fissure routes. The risks are attributable to the presence of large lacunae that receive multiple veins (type 2) or venous complex (type 3) configurations that negatively impact a surgeon's working space and degree of movement and thus are predisposed to inadvertent avulsions, bleeding, and venous thrombosis.

Comparative Anatomic Analysis of Neuronavigated Transmastoid-Infralabyrinthine Approaches for Jugular Fossa Pathologies: Short Anterior Rerouting Versus Nonrerouting and Tailored Nonrerouting Techniques.

BACKGROUND AND OBJECTIVES: Access to the jugular fossa pathologies (JFPs) via the transmastoid infralabyrinthine approach (TI-A) using the nonrerouting technique (removing the bone anterior and posterior to the facial nerve while leaving the nerve protected within the fallopian canal) or with the short-rerouting technique (rerouting the mastoid segment of the facial nerve anteriorly) has been described in previous studies. The objective of this study is to compare the access to Fisch class C lesions (JFPs extending or destroying the infralabyrinthine and apical compartment of the temporal bone with or without involving the carotid canal) between the nonrerouting and the short-rerouting techniques. Also, some tailored steps to the nonrerouting technique (NR-T) were outlined to enhance access to the jugular fossa (JF) as an alternative to the short-rerouting technique. METHODS: Neuronavigated TI-A was performed using the nonrerouting, tailored nonrerouting, and short-rerouting techniques on both sides of 10 human head specimens. Exposed area, horizontal distance, surgical freedom, and horizontal angle were calculated using vector coordinates for nonrerouting and short-rerouting techniques. RESULTS: The short-rerouting technique had significantly higher values than the NR-T ( P < .01) for the exposed area (169.1 ± SD 11.5 mm 2 vs 151.0 ± SD 12.4 mm 2 ), horizontal distance (15.9 ± SD 0.6 mm vs 10.6 ± SD 0.5 mm 2 ), surgical freedom (19 650.2 ± SD 722.5 mm 2 vs 17 233.8 ± SD 631.7 mm 2 ), and horizontal angle (75.2 ± SD 5.1° vs 61.7 ± SD 4.6°). However, adding some tailored steps to the NR-T permitted comparable access to the JF. CONCLUSION: Neuronavigated TI-A with the short-rerouting technique permits wider access to the JF compared with the NR-T. However, the tailored NR-T provides comparable access to the JF and may be a better option for class C1 and selected class C2 and C3 JFPs.