Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity.

Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington's disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances the fibrillization of and interacts with mutant thioredoxin (Trx)-fused Httex1. NMR studies with Htt peptides show that TrxHttex1-39Q interacts with the helical regions in SERF1a and SERF1a preferentially interacts with the N-terminal 17 residues of Htt. Time-course analysis shows that SERF1a induces mutant TrxHttex1 to a single conformation enriched of ß-sheet. Co-expression of SERF1a and Httex1-polyQ in neuroblastoma and lentiviral infection of SERF1a in HD-induced polypotent stem cell (iPSC)-derived neurons demonstrates the detrimental effect of SERF1a in HD. Higher level of SERF1a transcript or protein is detected in HD iPSC, transgenic mice, and HD plasma. Overall, this study provides molecular mechanism for SERF1a and mutant Httex1 to facilitate therapeutic development for HD.

Estimating the daily average concentration variations of PCDD/Fs in Taiwan using a novel Geo-AI based ensemble mixed spatial model.

It is generally established that PCDD/Fs is harmful to human health and therefore extensive field research is necessary. This study is the first to use a novel geospatial-artificial intelligence (Geo-AI) based ensemble mixed spatial model (EMSM) that integrates multiple machine learning algorithms and geographic predictor variables selected using SHapley Additive exPlanations (SHAP) values to predict spatial-temporal fluctuations in PCDD/Fs concentrations across the entire island of Taiwan. Daily PCDD/F I-TEQ levels from 2006 to 2016 were used for model construction, while external data was used for validating model dependability. We utilized Geo-AI, incorporating kriging, five machine learning, and ensemble methods (combinations of the aforementioned five models) to develop EMSMs. The EMSMs were used to estimate long-term spatiotemporal variations in PCDD/F I-TEQ levels, considering in-situ measurements, meteorological factors, geospatial predictors, social and seasonal influences over a 10-year period. The findings demonstrated that the EMSM was superior to all other models, with an increase in explanatory power reaching 87 %. The results of spatial-temporal resolution show that the temporal fluctuation of PCDD/F concentrations can be a result of weather circumstances, while geographical variance can be the result of urbanization and industrialization. These results provide accurate estimates that support pollution control measures and epidemiological studies.

Ganglioside-focused Glycan Array Reveals Abnormal Anti-GD1b Auto-antibody in Plasma of Preclinical Huntington's Disease.

Huntington's disease (HD) is a progressive and devastating neurodegenerative disease marked by inheritable CAG nucleotide expansion. For offspring of HD patients carrying abnormal CAG expansion, biomarkers that predict disease onset are crucially important but still lacking. Alteration of brain ganglioside patterns has been observed in the pathology of patients carrying HD. Here, by using a novel and sensitive ganglioside-focused glycan array, we examined the potential of anti-glycan auto-antibodies for HD. In this study, we collected plasma from 97 participants including 42 control (NC), 16 pre-manifest HD (pre-HD), and 39 HD cases and measured the anti-glycan auto-antibodies by a novel ganglioside-focused glycan array. The association between plasma anti-glycan auto-antibodies and disease progression was analyzed using univariate and multivariate logistic regression. The disease-predictive capacity of anti-glycan auto-antibodies was further investigated by receiver operating characteristic (ROC) analysis. We found that anti-glycan auto-antibodies were generally higher in the pre-HD group when compared to the NC and HD groups. Specifically, anti-GD1b auto-antibody demonstrated the potential for distinguishing between pre-HD and control groups. Moreover, in combination with age and the number of CAG repeat, the level of anti-GD1b antibody showed excellent predictability with an area under the ROC curve (AUC) of 0.95 to discriminate between pre-HD carriers and HD patients. With glycan array technology, this study demonstrated abnormal auto-antibody responses that showed temporal changes from pre-HD to HD.

Rationally designed divalent caffeic amides inhibit amyloid-ß fibrillization, induce fibril dissociation, and ameliorate cytotoxicity.

One of the pathologic hallmarks in Alzheimer's disease (AD) is extracellular senile plaques composed of amyloid-ß (Aß) fibrils. Blocking Aß self-assembly or disassembling Aß aggregates by small molecules would be potential therapeutic strategies to treat AD. In this study, we synthesized a series of rationally designed divalent compounds and examined their effects on Aß fibrillization. A divalent amide (2) derived from two molecules of caffeic acid with a propylenediamine linker of ∼5.0 Šin length, which is close to the distance of adjacent ß sheets in Aß fibrils, showed good potency to inhibit Aß(1-42) fibrillization. Furthermore, compound 2 effectively dissociated the Aß(1-42) preformed fibrils. The cytotoxicity induced by Aß(1-42) aggregates in human neuroblastoma was reduced in the presence of 2, and feeding 2 to Aß transgenic C. elegans rescued the paralysis phenotype. In addition, the binding and stoichiometry of 2 to Aß(1-40) were demonstrated by using electrospray ionization-traveling wave ion mobility-mass spectrometry, while molecular dynamic simulation was conducted to gain structural insights into the Aß(1-40)-2 complex.

Alzheimer's amyloid-ß A2T variant and its N-terminal peptides inhibit amyloid-ß fibrillization and rescue the induced cytotoxicity.

Alzheimer's disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-ß peptide (Aß). Several familial mutations found in Aß sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aß, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aß shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aß40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aß, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Aß. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aß fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Aß aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.

Curcumin affects development of zebrafish embryo.

Embryotoxic and teratogenic effects of curcumin on the development of zebrafish embryo were investi-gated in this study. The LD(50) values of curcumin (24-h incubation) were estimated at 7.5 microM and 5 microM for embryos and larvae, respectively. The developmental defects caused by curcumin treatments include bent or hook-like tails, spinal column curving, edema in pericardial sac, retarded yolk sac resorption, and shorter body length. In curcumin-treated larvae, fluorescence signals of curcumin were found in edamae sac and some skin cells. Together, these results indicate that zebrafish are suitable model organisms to study the toxic effects of curcumin.