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Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson’s disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T 4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists. Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.

An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein. However, the in vitro aggregation of α-syn is exceedingly slow and highly irreproducible, therefore precluding fast high throughput anti-aggregation drug screening. Here, we present a simple and easy-to-implement in-plate method for screening large chemical libraries in the search for α-syn aggregation modulators. It allows us to monitor aggregation kinetics with high reproducibility, while being faster and requiring lower protein amounts than conventional aggregation assays. We illustrate how the approach enables the identification of strong aggregation inhibitors in a library of more than 14,000 compounds.

Spirulina platensis (SPI) is a cyanobacterium , presenting anti-inflammatory and antioxidant actions. Considering the importance of inflammation and oxidative stress in Parkinson’s disease (PD), SPI neuroprotective effects were evaluated in a model of PD. Male Wistar rats were divided into: sham-operated (SO), untreated 6-OHDA and 6-OHDA treated with SPI (25 and 50 mg/kg, p.o.). The 6-OHDA was injected into the right striata and SPI treatments started 24 h later for 2 weeks. The SO and untreated 6-OHDA-lesioned groups were administered with distilled water, for the same period. Afterwards, the animals were subjected to the apomorphine-induced rotational test and euthanized for striatal measurements of DA and DOPAC, nitrite and TBARS and immunohistochemistry assays for TH, DAT, iNOS and COX-2. SPI reduced the apomorphine-induced rotational behavior, DA and DOPAC depletions and nitrite and TBARS increases, at its high dose. Furthermore, TH and DAT immunoreactivities in the lesioned striatum of the untreated 6-OHDA-lesioned group were attenuated by SPI. Similarly, immunoreactivities for iNOS and COX-2 were also decreased after SPI treatments. In conclusion, we showed that behavioral and neurochemical alterations in hemiparkinsonian rats were partly reversed by SPI, characterizing the neuroprotective potential of Spirulina and stimulating translational studies focusing on its use as an alternative treatment for PD.

[...]the C-terminal domain (residues 96–140) is rich in acidic and disorder-promoting residues, counteracting the tendency to aggregate of the NAC domain. [...]human H4 cells incubated with α-synCC presented only small size intracellular inclusions, in contrast to the large aggregates observed for wt α-syn. [...]they evaluated if the oligomers produced by wt α-syn and α-synCC were toxic for neuroblastoma cells. The oligomers were generated in conditions reported to form toxic species and, while this was true for wt α-syn oligomers, α-synCC oligomers did not affect cell viability. Since the morphological characteristics of the oligomers did not seem to explain this difference, as they were mostly similar, the authors proposed that the monomers interact through the NAC domain to form oligomers with a toxic structure, an observation that is also supported by other studies.

α-Synuclein (α-Syn) forms toxic intracellular protein inclusions and transmissible amyloid structures in Parkinson's disease (PD). Preventing α-Syn self-assembly has become one of the most promising approaches in the search for disease-modifying treatments for this neurodegenerative disorder. Here, we describe the capacity of a small molecule (ZPD-2), identified after a high-throughput screening, to inhibit α-Syn aggregation. ZPD-2 inhibits the aggregation of α-Syn and the A30P and H50Q familial variants at substoichiometric compound:protein ratios. In addition, the molecule prevents the spreading of α-Syn seeds in protein misfolding cyclic amplification assays. ZPD-2 is active against different α-Syn strains and blocks their seeded polymerization. Treating with ZPD-2 two different PD models that express α-Syn either in muscle or in dopaminergic (DA) neurons substantially reduces the number of α-Syn inclusions and decreases synuclein-induced DA neurons degeneration. Overall, ZPD-2 is a hit compound worth to be explored in order to develop lead molecules for therapeutic intervention in PD.

The interest in the diversity of yeasts in the Antarctic environment has increased in recent years, mainly because Antarctic microbiology is a recent science, and little is known about the biodiversity and genetic resources of the microorganisms that inhabit this ecosystem. This study aimed to determine the diversity of epiphytic yeasts in samples of Deschampsia antarctica, Colobanthus quitensis, and bryophytes, as well yeasts present in biofilms collected from Antarctic meltwater. Samples were collected in the summer of 2014 and 2015 during expeditions organized by the Brazilian Antarctic Program. A total of 310 yeasts were isolated, and 34 species were identified by sequencing the D1/D2 domains of the rDNA region belonging to 18 genera. The species Vishniacozyma victoriae and Mrakia gelida were the most abundant. Dioszegia antarctica and Leucosporidium creatinivorum were found only in plant substrates. Most psychrophilic yeasts were isolated from biofilms, including Glaciozyma antarctica, Glaciozyma martinii, Mrakia gelida, Mrakia frigida, Mrakia robertii, Phenoliferia glacialis, and Phenoliferia psychrophenolica, suggesting that the substrates examined in this study represented an interesting habitat for the isolation and characterization of epiphytic and non-epiphytic yeasts that colonize the Antarctic region.

The aggregation of proteins compromises cell fitness, either because it titrates functional proteins into non-productive inclusions or because it results in the formation of toxic assemblies. Accordingly, computational proteome-wide analyses suggest that prevention of aggregation upon misfolding plays a key role in sequence evolution. Most proteins spend their lifetimes in a folded state; therefore, it is conceivable that, in addition to sequences, protein structures would have also evolved to minimize the risk of aggregation in their natural environments. By exploiting the AGGRESCAN3D structure-based approach to predict the aggregation propensity of >600 Escherichia coli proteins, we show that the structural aggregation propensity of globular proteins is connected with their abundance, length, essentiality, subcellular location and quaternary structure. These data suggest that the avoidance of protein aggregation has contributed to shape the structural properties of proteins in bacterial cells.

Reports on phase separation and amyloid formation for multiple proteins and aggregation-prone peptides are recurrently used to explore the molecular mechanisms associated with several human diseases. The information conveyed by these reports can be used directly in translational investigation, e.g., for the design of better drug screening strategies, or be compiled in databases for benchmarking novel aggregation-predicting algorithms. Given that minute protocol variations determine different outcomes of protein aggregation assays, there is a strong urge for standardized descriptions of the different types of aggregates and the detailed methods used in their production. In an attempt to address this need, we assembled the Minimum Information Required for Reproducible Aggregation Experiments (MIRRAGGE) guidelines, considering first-principles and the established literature on protein self-assembly and aggregation. This consensus information aims to cover the major and subtle determinants of experimental reproducibility while avoiding excessive technical details that are of limited practical interest for non-specialized users. The MIRRAGGE table (template available in Supplementary Information ) is useful as a guide for the design of new studies and as a checklist during submission of experimental reports for publication. Full disclosure of relevant information also enables other researchers to reproduce results correctly and facilitates systematic data deposition into curated databases.

Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson’s Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of α-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.