Search

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, we used ascorbate peroxidase (APEX) proximity labeling, mass spectrometry, and immunofluorescence to identify ∼150 previously unknown human SG components. A highly integrated, pre-existing SG protein interaction network in unstressed cells facilitates rapid coalescence into larger SGs. Approximately 20% of SG diversity is stress or cell-type dependent, with neuronal SGs displaying a particularly complex repertoire of proteins enriched in chaperones and autophagy factors. Strengthening the link between SGs and neurodegeneration, we demonstrate aberrant dynamics, composition, and subcellular distribution of SGs in cells from amyotrophic lateral sclerosis (ALS) patients. Using three Drosophila ALS/FTD models, we identify SG-associated modifiers of neurotoxicity in vivo. Altogether, our results highlight SG proteins as central to understanding and ultimately targeting neurodegeneration.

This study aimed to develop a multi-long noncoding RNA (lncRNA) signature for the prediction of gastric cancer (GC) based on differential gene expression between recurrence and nonrecurrence patients.

GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR)80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR)80 or (GR)80-induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR)80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD.

Hypericin can be derived from St. John's wort, which is widely spread around the world. As a natural product, it has been put into clinical practice such as wound healing and depression for a long time. In this article, we review the pharmacology, pharmacokinetics, and safety of hypericin, aiming to introduce the research advances and provide a full evaluation of it. Turns out hypericin, as a natural photosensitizer, exhibits an excellent capacity for anticancer, neuroprotection, and elimination of microorganisms, especially when activated by light, potent anticancer and antimicrobial effects are obtained after photodynamic therapy. The mechanisms of its therapeutic effects involve the induction of cell death, inhibition of cell cycle progression, inhibition of the reuptake of amines, and inhibition of virus replication. The pharmacokinetics properties indicate that hypericin has poor water solubility and bioavailability. The distribution and excretion are fast, and it is metabolized in bile. The toxicity of hypericin is rarely reported and the conventional use of it rarely causes adverse effects except for photosensitization. Therefore, we may conclude that hypericin can be used safely and effectively against a variety of diseases. We hope to provide researchers with detailed guidance and enlighten the development of it. [ABSTRACT FROM AUTHOR]

Although the pathogenesis of Parkinson's disease (PD) remains unclear, mutations in leucine-rich repeat kinase 2 (Lrrk2) are among the major causes of familial PD. Most of these mutations disrupt Lrrk2 kinase and (or) GTPase domain function, resulting in neuronal degeneration. However, the signal pathways underlying Lrrk2-induced neuronal degeneration are not fully understood. There is an expanding body of evidence that suggests a link between Lrrk2 function and MAP kinase (MAPK) cascades. To further investigate this link in vivo, genetic RNAi screens of the MAPK pathways were performed in a Drosophila model to identify genetic modifier(s) that can suppress G2019S-Lrrk2-induced PD-like phenotypes. The results revealed that the knockdown of hemipterous (hep, or JNKK) increased fly survival time, improved locomotor function, and reduced loss of dopaminergic neurons in G2019S-Lrrk2 transgenic flies. Expression of the dominant-negative allele of JNK (JNK-DN), a kinase that is downstream of hep in G2019S-Lrrk2 transgenic flies, elicited a similar effect. Moreover, treatment with the JNK inhibitor SP600125 partially reversed the G2019S-Lrrk2-induced loss of dopaminergic neurons. These results indicate that the hep pathway plays an important role in Lrrk2-linked Parkinsonism in flies. These studies provide new insights into the molecular mechanisms underlying Lrrk2-linked PD pathogenesis and aid in identifying potential therapeutic targets. Key words: Lrrk2, Parkinson's disease, JNK, neuronal degeneration, hep, dopamine neuron, Drosophila model. Meme si la pathogenese de la maladie de Parkinson (MP) demeure floue, des mutations de la proteine Lrrk2 (leucine riche repeat kinase 2) sont parmi les principales causes de la MP hereditaire. La plupart de ces mutations dereglent la fonction des domaines kinase ou GTPase de Lrrk2, resultant en une degeneration neuronale. Toutefois, les voies de signalisation qui sous-tendent la degeneration neuronale induite par Lrrk2 ne sont pas completement comprises. Ilyadeplus en plus de donnees qui suggerent qu'il existe un lien entre la fonction de Lrrk2 et les cascades des MAP kinases (MAPK). Afin d'approfondir ce lien in vivo, des criblages genetiques des voies des MAPK a l'aide d'ARNi ont ete realises chez la drosophile afin d'identifier les modificateurs genetiques qui peuvent supprimer les phenotypes de type parkinsonien induits par G2019S-Lrrk2. Les resultats ont revele que le knockdown de hemipterous (hep ou JNKK) accroissait la duree de vie des mouches, ameliorait la fonction locomotrice et reduisait la perte de neurones dopaminergiques chez les mouches transgeniques G2019S-Lrrk2. L'expression de l'allele dominant negatif de JNK (JNK-DN), une kinase qui agit en aval de hep chez les mouches transgeniques G2019S-Lrrk2, provoquait un effet similaire. De plus, un traitement avec l'inhibiteur de JNK SP600125 renversait partiellement la perte de neurones dopaminergiques induite par G2019S-Lrrk2. Ces resultats indiquent que la voie de hep joue un role important dans le parkinsonisme lie a Lrrk2 chez les mouches. Ces etudes apportent un eclairage nouveau sur les mecanismes moleculaires qui sous-tendent la pathogenese de la MP liee a Lrrk2 et contribuent a identifier des cibles therapeutiques potentielles. [Traduit par la Redaction] Mots-cles : Lrrk2, maladie de Parkinson, JNK, degeneration neuronale, hep, neurone a dopamine, modele de la drosophile., Introduction Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The clinical [...]

Glucose oxidase (GOx) has attracted a lot of attention in the field of diabetes diagnosis and treatment in recent years owing to its inherent biocompatibility and glucose-specific catalysis. GOx can effectively catalyze the oxidation of glucose in the blood to hydrogen peroxide (H2O2) and glucuronic acid and can be used as a sensitive element in biosensors to detect blood glucose concentrations. Nanomaterials based on the immobilization of GOx can significantly improve the performance of glucose sensors through, for example, reduced electron tunneling distance. Moreover, various insulin-loaded nanomaterials (e.g., metal–organic backbones, and mesoporous silica nanoparticles) have been developed for the control of blood glucose concentrations based on GOx catalytic chemistry. These nano-delivery carriers are capable of releasing insulin in response to GOx-mediated changes in the microenvironment, allowing for a rapid return of the blood microenvironment to a normal state. Therefore, glucose biosensors and insulin delivery vehicles immobilized with GOx are important tools for the diagnosis and treatment of diabetes. This paper reviews the characteristics of various GOx-based nanomaterials developed for glucose biosensing and insulin-responsive release as well as research progress, and also highlights the current challenges and opportunities facing this field. [ABSTRACT FROM AUTHOR]