Alexander disease:the road ahead

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

Penumbra-targeted CircOGDH siRNA-loaded nanoparticles alleviate neuronal apoptosis in focal brain ischaemia

Background Nanoparticles(NPs)are a class of substances that can be loaded with therapeutic agents delivered to specific areas.In our earlier research,we identified a neuron-derived circular RNA(circRNA),circular oxoglutarate dehydrogenase(CircOGDH),as a promising therapeutic target for acute ischaemic stroke.This study dedicated to explore a prospective preliminary strategy of CircOGDH-based NP delivered to the ischaemic penumbra region in middle cerebral artery occlusion/reperfusion(MCAO/R)mice.Methods Immunofluorescence in primary cortex neurons and in vivo fluorescence imaging revealed endocytosis of Poly(lactide-co-glycolide)(PLGA)poly amidoamine(PAMAM)@CircOGDH small interfering RNA(siRNA)NPs.Western blotting analysis and CCK8 assay were performed to evaluate the apoptotic level in ischaemic neurons treated with PLGA–PAMAM@CircOGDH siRNA NPs.Quantitative reverse transcription PCR experiments,mice behaviour test,T2 MRI analysis,Nissl and TdT-mediated dUTP nick end labeling(TUNEL)co-staining were performed to evaluate the apoptosis level of ischaemic penumbra neurons in MCAO/R mice.Biosafety evaluation of NPs in MCAO/R mice was detected by blood routine examination,liver and kidney function examination and HE staining.Results PLGA–PAMAM@CircOGDH siRNA NPs were successfully assembled.Endocytosis of PLGA–PAMAM@CircOGDH siRNA NPs in ischaemic neurons alleviated neuronal apoptotic level in vitro and in vivo.Furthermore,mice behaviour test showed that the neurological defects of MCAO/R mice were significantly alleviated after the tail injection of PLGA–PAMAM@CircOGDH siRNA NPs,and no toxic effects were observed.Conclusion In conclusion,our results suggest that PLGA–PAMAM@CircOGDH siRNA NPs can be delivered to the ischaemic penumbra region and alleviate neuron apoptosis in MCAO/R mice and in ischaemic neurons;therefore,our study provides a desirable approach for using circRNA-based NPs for the treatment of ischaemic stroke.

Catquest-9SF functioning over a decade–a study from the Swedish National Cataract Register

Background:The Swedish National Cataract Register(NCR)collects data on cataract surgery outcomes during March,including patient-reported outcomes using the Catquest-9SF questionnaire for over 11 years.Previous studies from NCR have shown that the preoperative visual acuity has improved over time.The main purpose of this study was to evaluate the Catquest-9SF Rasch scoring performance in this changing environment.A second purpose was to describe clinical data over the same period for those who completed the questionnaire.Methods:The performance of the Catquest-9SF was analysed by a separate Rasch analysis for each year,resulting in a preoperative and postoperative score for each participating patient in the annual cohorts.The clinical data and questionnaire scoring were analysed for each year in the period 2008-2018 inclusive.Results:Data were available for 42,023 eyes for 11 annual cohorts(2008-2018).The psychometric properties of the questionnaire were stable during the study period.Person separation(precision)for the whole period was 2.58 and varied between 2.45 and 2.72.The person reliability was 0.87 and varied between 0.86 and 0.88.The targeting of question difficulty to person ability became less accurate over time meaning that the item activities became easier to carry out without difficulty.The average targeting for the whole period was−2.06 and changed from−1.92 in 2008 to−2.31 in 2018.The person score improved both before surgery and after surgery,indicating that patients are undergoing surgery at a more able level and getting better outcomes.The average improvement by surgery decreased from 3.41 logits in 2008 to 3.21 logits in 2018(p=0.003).Over time,patient age decreased from 75 to 74 years(p<0.001)and the proportion of women decreased from 63.9 to 57.9%(p<0.001).The mean preoperative visual acuity in both the operated eye and the better eye improved over time(0.47 to 0.40 logMAR,p<0.001 and 0.22 to 0.19 logMAR,p<0.001,respectively),as did the mean postoperative visual acuity in the operated eye(0.14 to 0.09 logMAR,p<0.001).Conclusions:The Catquest-9SF retained stable psychometric properties over this 11-year period although more recent cohorts included slightly younger patients with somewhat better vision.