A separation-free paper-based hydrogel device for one-step reactive oxygen species determination by a smartphone.

Paper-based analytical devices (PADs) are very convenient for determining biomarkers in point-of-care (POC) diagnosis while requiring sample pre-treatment or impurity separation. This study reports a novel hydrogel-coupled, paper-based analytical device (PAD) for separation-free H2O2 colorimetric detection in both aqueous solution and cell lysis with sample-to-answer analysis by directly loading into the sample test zone. By encapsulating an inorganic mimic enzyme and chromogenic substrate into the sodium alginate (SA) hydrogel, amplification of the color signal after catalyzing the substrate could be achieved. Taking advantage of the nanoscale porous structure of the hydrogel and the lateral flow channel of the PAD, large interference fragments or bio-macromolecules are prevented from diffusing into the chromogenic reaction, whereas the small target molecules enter the sensing region to trigger the catalytic reaction. This method demonstrated a rapid and accurate analysis with a limit of detection as low as 0.06 mM and detection selectivity. Our proposed device requires no enzyme and is separation-free, portable, easy-to-fabricate, and low-cost, and may offer a platform for quantitative or qualitative analysis of other analytes in body fluids for POC applications.

ß-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the world, and synuclein is closely related to the onset and progression of PD. Synuclein is considered a therapeutic target for PD. Recent studies have found that abnormal aggregation of α-synuclein (α-Syn) in the brains of PD patients leads to mitochondrial dysfunction and neuroinflammation. Research in the field of neuroscience has confirmed that ß-synuclein (ß-Syn) also plays a role in Parkinson's disease. However, there has been little research on the role mechanisms and interactions between ß-Syn and α-Syn in PD. Therefore, the purpose of this study is to clarify the relationship between α-Syn, ß-Syn, and PD and to explore the roles and interactions of ß-Syn and α-Syn in PD.

Role of Inflammation in the Development of COVID-19 to Parkinson's Disease.

Background: The coronavirus disease 2019 (COVID-19) can lead to neurological symptoms such as headaches, confusion, seizures, hearing loss, and loss of smell. The link between COVID-19 and Parkinson's disease (PD) is being investigated, but more research is needed for a definitive connection. Methods: Datasets GSE22491 and GSE164805 were selected to screen differentially expressed gene (DEG), and immune infiltration and gene set enrichment analysis (GSEA) of the DEG were performed. WGCNA analyzed the DEG and selected the intersection genes. Potential biological functions and signaling pathways were determined, and diagnostic genes were further screened using gene expression and receiver operating characteristic (ROC) curves. Screening and molecular docking of ibuprofen as a therapeutic target. The effectiveness of ibuprofen was verified by constructing a PD model in vitro, and constructing "COVID19-PD" signaling pathway, and exploring the role of angiotensin-converting enzyme 2 (ACE2) in PD. Results: A total of 13 DEG were screened from the GSE36980 and GSE5281 datasets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the DEG were mainly associated with the hypoxia-inducible factor (HIF-1), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, etc. After analysis, it is found that ibuprofen alleviates PD symptoms by inhibiting the expression of nuclear factor kappa-B (NF-κB), interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α). Based on signal pathway construction, the importance of ACE2 in COVID-19-induced PD has been identified. ACE2 is found to have widespread distribution in the brain. In the 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced ACE2-null PD mice model, more severe motor and non-motor symptoms, increased NF-κB p65 and α-synuclein (α-syn) expression with significant aggregation, decreased tyrosine hydroxylase (TH), severe neuronal loss, and neurodegenerative disorders. Conclusion: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of PD through an inflammatory environment and downregulation of ACE2, providing evidence for the molecular mechanism and targeted therapy associated with COVID-19 and PD.

Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.

Clinical value and mechanistic analysis of HIIT on modulating risk and symptoms of depression: A systematic review.

Background: The exact causal mechanisms of depression remain unclear due to the complexity of the triggers, which has led to limitations in treating depression using modern drugs. High-intensity interval training (HIIT) is as effective as medication in treating depression without toxic side effects. Typically, HIIT requires less time commitment (i.e., shorter exercise duration) and exhibits pronounced benefits on depressive symptoms than other forms of physical exercise. This review summarizes the risk reduction and clinical effects of HIIT for depression and discusses the underlying mechanisms, providing a theoretical basis for utilizing HIIT in treating depression. Methods: A database search was conducted in PubMed, Embase, Web of Science, and Scopus from inception up to October 2022. The methodological quality of the included literature was evaluated by the physiotherapy evidence database (PEDro) scale criteria. The review focused on evaluating the changes in depression risk or symptoms of HIIT interventions in healthy individuals, patients with depression, and patients with other disorders co-morbid with depression. Consequently, the mechanisms associated with depression related HIIT were summarized. Results: A total of 586 participants (52 % female; mean age: 43.58±8.93 years) from 22 studies were included. Implementing HIIT using different exercise types alleviates depressive symptoms in individuals with depression and in individuals with depression who have exhibited comorbidities and reduced depression scale scores in subjects immediately after acute exercise. In addition, the long-interval HIIT and short-interval HIIT in the treatment of patients with cardiovascular or psychiatric disorders may reduce depressive symptoms via complex exercise-related changes on several levels, including by effecting the following measures: releasing monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body. Conclusion: HIIT is a relatively safe and effective antidepressant, which may involve multiple neurobiological mechanisms (release of monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body), thereby reducing the risk or symptoms of depression in participants.

Integrative Analysis of the Role of TP53 in Human Pan-Cancer.

Tumor protein P53 (TP53) is an important tumor suppressor gene in humans. Under normal circumstances, TP53 can help repair mutated genes, or promote the death of cells with severe gene mutations (specifically, TP53 prevents cells from arrest in the G1/S phase when deoxyribonucleic acid (DNA) is damaged and promotes apoptosis if not repaired), and prevents normal cells from becoming malignant cells. TP53 mutations affect its tumor suppressor function, leading to the development of malignant tumors. In this study, using a public database, we explored the pan-cancer expression of TP53, its impact on patient survival and prognosis, the types of gene mutations, its correlation with immunity, and its regulation of other transcription factors and micro RNA (miRNA). The docking sites of therapeutic drugs and key amino acid sites of action provide a basis for future targeted therapies. TP53 has important biological functions in the human body. This study provides a theoretical basis for clinical TP53 gene therapy.

The Construction and Validation of a Novel Ferroptosis-Related Gene Signature in Parkinson's Disease.

As a newly discovered regulated cell death mode, ferroptosis is associated with the development of Parkinson's disease (PD) and has attracted much attention. Nonetheless, the relationship between ferroptosis and PD pathogenesis remains unclear. The GSE8397 dataset includes GPL96 and GPL97 platforms. The differential genes were analyzed by immune infiltration and Gene Set Enrichment Analysis (GSEA) (p < 0.05), and differential multiple |logFC| > 1 and weighted gene coexpression network analysis (WGCNA) were used to screen differential expression genes (DEGs). The intersection with 368 ferroptosis-related genes (FRGs) was conducted for gene ontology/Kyoto encyclopedia of gene and genome (GO/KEGG) enrichment analysis, gene expression analysis, correlation analysis, single-cell sequencing analysis, and prognosis analysis (area under the curve, AUC) and to predict relevant miRNAs and construct network diagrams using Cytoscape. The intersection genes of differentially expressed ferroptosis-related genes (DEFRGs) and mitochondrial dysfunction genes were validated in the substantia nigra of MPTP-induced PD mice models by Western blotting and immunohistochemistry, and the protein-binding pocket was predicted using the DoGSiteScorer database. According to the results, the estimated scores were positively correlated with the stromal scores or immune scores in the GPL96 and GPL97 platforms. In the GPL96 platform, the GSEA showed that differential genes were mainly involved in the GnRH signaling pathway, B cell receptor signaling pathway, inositol phosphate metabolism, etc. In the GPL97 platform, the GSEA showed that differential genes were mainly involved in the ubiquitin-mediated proteolysis, axon guidance, Wnt signaling pathway, MAPK signaling pathway, etc. We obtained 26 DEFRGs, including 12 up-regulated genes and 14 down-regulated genes, with good correlation. The area under the prognostic analysis curve (AUC > 0.700) showed a good prognostic ability. We found that they were enriched in different neuronal cells, oligodendrocytes, astrocytes, oligodendrocyte precursor cells, and microglial cells, and their expression scores were positively correlated, and selected genes with an AUC curve ≥0.9 were used to predict miRNA, including miR-214/761/3619-5p, miR-203, miR-204/204b/211, miR-128/128ab, miR-199ab-5p, etc. For the differentially expressed ferroptosis-mitochondrial dysfunction-related genes (DEF-MDRGs) (AR, ISCU, SNCA, and PDK4), in the substantia nigra of mice, compared with the Saline group, the expression of AR and ISCU was decreased (p < 0.05), and the expression of α-Syn and PDK4 was increased (p < 0.05) in the MPTP group. Therapeutic drugs that target SNCA include ABBV-0805, Prasinezumab, Cinpanemab, and Gardenin A. The results of this study suggest that cellular DEF-MDRGs might play an important role in PD. AR, ISCU, SNCA, and PDK4 have the potential to be specific biomarkers for the early diagnosis of PD.

Validation of a Novel Cuproptosis-Related Prognostic Gene Marker and Differential Expression Associated with Lung Adenocarcinoma.

BACKGROUND: Cuproptosis induction is seen as a promising alternative for immunotherapies and targeted therapies in breast cancer. The objective of this research was to examine the prognostic and biological importance of cuproptosis-related genes (CRGs) in lung adenocarcinoma (LUAD). METHODS: The following methods were used: GSE10072 dataset and TCGA database analysis, differential expression analysis of CRGs, and biological function (BP) and signaling pathway enrichment analysis, prognostic analysis and clinical analysis of CRGs, construction of the prognostic signature and RNA modified genes and miRNA analysis of CRGs in LUAD, immunoinfiltration analysis and immunohistochemical staining of DßH, UBE2D3, SOD1, UBE2D1 and LOXL2. RESULTS: AOC1, ATOX1, CCL8, CCS, COX11, CP, LOXL2, MAP2K2, PDK1, SCO2, SOD1, UBE2D1, UBE2D3 and VEGFA showed significantly higher expression, while ATP7B, DßH, PDE3B, SLC31A2, UBE2D2, UBE2D4 and ULK2 showed lower expression in LUAD tissues than normal tissues. We also found that ATP7B (4%), AOC1 (3%) PDE3B (2%), DßH (2%), CP (1%), ULK2 (1%), PDK1 (1%), LOXL2 (1%) and UBE2D3 (1%) showed higher mutation frequencies. The univariate Cox analysis was used to identify CRGs that have prognostic value. It identified 21 genes that showed significant prognostic value, containing DßH, UBE2D3, SOD1, UBE2D1 and LOXL2. Patients with DßH up-expression have a longer survival time and patients with UBE2D3, SOD1, UBE2D1 and LOXL2 down-expression also have a longer survival time. hsa-miR-29c-3p, hsa-miR-29a-3p, hsa-miR-181c-5p, hsa-miR-1245a, etc., play an important role in the miRNA regulatory network, and in LUAD, miR-29a, miR-29c and miR-181c high expression survival was longer, and miR-1245a low expression survival was longer. We also performed an analysis to examine the relationships between DßH, LOXL2, SOD1, UBE2D1 and UBE2D3 and immune infiltration in LUAD, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs. CONCLUSION: DßH, UBE2D3, SOD1, UBE2D1, and LOXL2 are potential candidates implicated in LUAD and can be further explored for their application as diagnostic, prognostic, and therapeutic biomarkers for LUAD.

How do Mutations of Mycobacterium Genes Cause Drug Resistance in Tuberculosis?

A steady increase in the prevalence of drug-resistant tuberculosis (DR-TB) has already been reported in Pakistan. In addition, DR-TB is gradually changing from one-drug resistance to multi-drug resistance, which is a serious challenge for tuberculosis treatment. This review provides an overview of the anti-tuberculosis drugs and focuses on the molecular mechanisms of drug resistance in Mycobacterium tuberculosis, with the hope that it will contribute to the study of drug resistance in response to the emergence of multidrug-resistant tuberculosis.

Liquid-liquid phase separation regulates alpha-synuclein aggregate and mitophagy in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, and alpha-synuclein (α-syn) abnormal aggregate and mitochondrial dysfunction play a crucial role in its pathological development. Recent studies have revealed that proteins can form condensates through liquid-liquid phase separation (LLPS), and LLPS has been found to be widely present in α-syn aberrant aggregate and mitophagy-related protein physiological processes. This review summarizes the occurrence of α-syn LLPS and its influencing factors, introduces the production and transformation of the related protein LLPS during PINK1-Parkin-mediated mitophagy, hoping to provide new ideas and methods for the study of PD pathology.

Dose-Response Relationships of Resistance Training in Adults With Knee Osteoarthritis: A Systematic Review and Meta-analysis.

BACKGROUND AND PURPOSE: To determine the effects of resistance training (RT) on symptoms, function, and lower limb muscle strength in patients with knee osteoarthritis (KOA), and to determine the optimal dose-response relationships. DATA SOURCES: We searched the PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and ClinicalTrials.gov databases from inception to January 23, 2022. ELIGIBILITY CRITERIA: Randomized controlled trials that examined the effects of RT in KOA patients (mean age ≥50 years) were included. DATA SYNTHESIS: We applied Hedges' g of the random-effects model to calculate the between-subject standardized mean difference (SMDbs). A random-effects metaregression was calculated to explain the influence of key training variables on the effectiveness of RT. We used the Grading of Recommendations Assessments, Development and Evaluation (GRADE) method to appraise the certainty of evidence. RESULTS: A total of 46 studies with 4289 participants were included. The analysis revealed moderate effects of RT on symptoms and function (SMDbs =-0.52; 95% CI: -0.64 to -0.40), and lower limb muscle strength (SMDbs = 0.53; 95% CI: 0.42 to 0.64) in the intervention group compared with the control group. The results of the metaregression revealed that only the variable "training period" (P< .001) had significant effects on symptoms, function, and lower limb muscle strength, and the 4 to 8 weeks of training subgroup showed greater effects than other subgroups (SMDbs =-0.70, -0.91 to -0.48; SMDbs = 0.76, 0.56 to 0.96). CONCLUSIONS: Compared with inactive treatments, RT is strongly recommended to improve symptoms, function, and muscle strength in individuals with KOA. Dose-response relationship analysis showed that 4 to 8 weeks of RT had more benefits.

The Role of Cellular Defense Systems of Ferroptosis in Parkinson's Disease and Alzheimer's Disease.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common rapidly developing neurodegenerative diseases that lead to serious health and socio-economic consequences. Ferroptosis is a non-apoptotic form of cell death; there is growing evidence to support the notion that ferroptosis is involved in a variety of pathophysiological contexts, and there is increasing interest in the role of ferroptosis in PD and AD. Simultaneously, cells may have evolved four defense systems to counteract the toxic effects of ferroptosis occasioned by lipid peroxidation. This review, which focuses on the analysis of ferroptosis in the PD and AD context, outlines four cellular defense systems against ferroptosis and how each of them is involved in PD and AD.

Elucidating the primary mechanisms of high-intensity interval training for improved cardiac fitness in obesity.

Obesity is a global and rising multifactorial pandemic associated with the emergence of several comorbidities that are risk factors for malignant cardiac remodeling and disease. High-intensity interval training (HIIT) has gained considerable attention due to its favorable outcomes of cardiometabolic health in individuals with overweight or obese. The primary aim of this review is to discuss the fundamental processes through which HIIT improves cardiac impairment in individuals with obesity to develop viable treatments for obesity management. In this review, a multiple database search and collection were conducted from the earliest record to January 2013 for studies included the qualitative component of HIIT intervention in humans and animals with overweight/obesity related to cardiac remodeling and fitness. We attempt to integrate the main mechanisms of HIIT in cardiac remolding improvement in obesity into an overall sequential hypothesis. This work focus on the ameliorative effects of HIIT on obesity-induced cardiac remodeling with respect to potential and pleiotropic mechanisms, including adipose distribution, energy metabolism, inflammatory response, insulin resistance, and related risk profiles in obesity. In conclusion, HIIT has been shown to reduce obesity-induced risks of cardiac remodeling, but the long-term effects of HIIT on obesity-induced cardiac injury and disease are presently unknown. Collective understanding highlights numerous specific research that are needed before the safety and effectiveness of HIIT can be confirmed and widely adopted in patient with obesity.

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.

Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

The potential bioactive ingredients and hub genes of five TCM prescriptions against lung adenocarcinoma were explored based on bioinformatics.

Analysis of the commonness of several prescriptions of traditional Chinese medicine (TCM) in the treatment of lung adenocarcinoma (LUAD) based on bioinformatics. Searched the TCM prescriptions for the treatment of LUAD in the literature published in the database, searched ingredients in the TCM through TCMSP and Swiss target prediction databases (OB ≥ 30%, DL > 0.18, Caco-2 > 0), and predicted the potential targets. GEO database retrieved LUAD gene chip data and screened (P < 0.05, | log2 (fold change) |> 1). The biological function, hub gene selection and survival period, immune infiltration, methylation, copy number variations (CNVs), and single-nucleotide variants (SNV) of hub genes were analyzed by DAVID, STRING, Kaplan-Meier plotter database, Cytoscape software, GSCALite database, and TIMER2.0. In this study, 5 TCM prescriptions were analyzed, and a total of 173 ingredients were obtained through database search, including 35 coincidence ingredients, a total of 603 potential targets, 621 LUAD-related genes, 16 up-regulated genes, and 31 down-regulated genes. A total of 61 terms of biological process (BP), 14 terms of cellular component (CC), and 14 terms of molecular function (MF) were obtained. Twenty core genes were obtained, including 15 genes with different survival periods, which were closely related to immune cells (B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cells). The low expression of ADRB2 and MAOA and the high expression of AUARK, CDK1, KIF11, MIF, TOP2A, and TTK were associated with the survival rate of LUAD patients (P < 0.05). Baicalein, Arachidonate, Hederagenin, and hub genes may become potential drugs and potential targets for LUAD treatment. Evaluated the efficacy of TCM in the treatment of LUAD from macro to micro, mined the hub genes, and predicted the mechanism of action, so as to lay the foundation for the development of new drugs of TCM, prescription optimization, or disease control.

Parkinson's Disease as a Risk Factor for Prostate Adenocarcinoma: A Molecular Point of View.

INTRODUCTION: Cancer and neurodegeneration are two major leading causes of morbidity and death worldwide. Neurodegeneration results in excessive neuronal cell death, and cancer emerges from increased proliferation and resistance to cell death. Although most epidemiological studies support an inverse association between the risk for the development of neurodegenerative diseases and cancer, increasing evidence points to a positive correlation between specific types of cancer, like prostate adenocarcinoma (PRAD), and neurodegenerative diseases, like Parkinson's disease (PD). METHODS: PD and PRAD differential genes were screened through the GEO database, and the differential genes were analyzed using David, String, GEPIA, Kaplan-Meier plotter, TIMER2.0, proteinatlas, cBioPortal, and CTD databases to elucidate the biological function and molecular mechanism of PD and PRAD-related genes. RESULTS: Studies have shown that the hub gene and differentially expressed genes (DEGs) in PD were differentially expressed in PRAD, including CDC20, HSPA4L, ROBO1, DMKN, IFI27L2, LUZP2, PTN, PTGDS. In PRAD, the high expression of HSPA4L, ROBO1, DMKN, IFI27L2, PTN, and PTGDS genes was associated with longer survival, while the patients with low expression of CDC20 and LUZP2 genes had longer survival. The mRNA of CDC20 and LUZP2 were highly expressed, while the mRNAs of HSPA4L, ROBO1, DMKN, IFI27L2, and PTGDS were low expressed. Gene methylation did not affect the survival of patients. The high expression of miR-142, miR-186, miR-30a, miR-497, miR-590, miR-28, and miR-576 in microRNA (miRNA) might potentially be used as biomarkers for the progression of PD and PRAD and for the early diagnosis of PD and PRAD in the populations. The genes in this study were highly associated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Somatic mutation mainly focused on missense mutation. Therapeutic drugs included acetaminophen and valproic acid (VPA). CONCLUSION: Bioinformatics was used to identify potential targets and novel molecular mechanisms that may serve as clinical markers for the diagnosis and treatment of PD and PRAD.

The reciprocal interactions between microglia and T cells in Parkinson's disease: a double-edged sword.

In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune cells exacerbates the disease process and leads to the pathological development of pro-inflammatory cytokines, chemokines, and contact-killing compounds, causing the loss of dopaminergic neurons. So far, we have mainly focused on the role of the specific class of immune cells in PD while neglecting the impact of interactions among immune cells on the disease. Therefore, this review demonstrates the reciprocal interplays between microglia and T cells and the associated subpopulations through cytokine and chemokine production that impair and/or protect the pathological process of PD. Furthermore, potential targets and models of PD neuroinflammation are highlighted to provide the new ideas/directions for future research.

Differential involvement of amyloidogenic evolvability in oligodendropathies; Multiple Sclerosis and Multiple System Atrophy.

Although multiple sclerosis (MS) and multiple system atrophy (MSA) are both characterized by impaired oligodendrocytes (OLs), the aetiological relevance remains obscure. Given inherent stressors affecting OLs, the objective of the present study was to discuss the possible role of amyloidogenic evolvability (aEVO) in these conditions. Hypothetically, in aEVO, protofibrils of amyloidogenic proteins (APs), including ß-synuclein and ß-amyloid, might form in response to diverse stressors in parental brain. Subsequently, the AP protofibrils might be transmitted to offspring via germ cells in a prion-like fashion. By virtue of the stress information conferred by protofibrillar APs, the OLs in offspring's brain might be more resilient to forthcoming stressors, perhaps reducing MS risk. aEVO could be comparable to a gene for the inheritance of acquired characteristics. On the contrary, during ageing, MSA risk is increased through antagonistic pleiotropy. Consistently, the expression levels of APs are reduced in MS, but are increased in MSA compared to controls. Furthermore, ß-synuclein, the non-amyloidogenic homologue of ß-synuclein, might exert a buffering effect on aEVO, and abnormal ß-synuclein could also increase MS and MSA disease activity. Collectively, a better understanding of the role of aEVO in the OL diseases might lead to novel interventions for such chronic degenerative conditions.

A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1.

BACKGROUND: Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown. RESULTS: We identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice. CONCLUSIONS: These results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.