Machado-Joseph disease (MJD, also known as spinocerebellar ataxia 3 or SCA3) is the most common dominant ataxia worldwide, with an overall average prevalence of 1–5/100,000. To this date, two major ancestral lineages have been found throughout the world. In China, the relative frequency of MJD among the SCAs reaches as high as 63%, however, little is known about its mutational origin in this country. We analyzed 50 families with MJD patients in two or more generations to study the hypothesis that new mutational events have occurred in this population. Haplotypes based on 20 SNPs have shown new genetic backgrounds segregating with MJD mutations in our cohort from China. We found the “Joseph-derived” lineage (Joseph lineage with a G variant in rs56268847) to be very common among Chinese MJD patients. Moreover, we estimated the time for the origin of this MJD SNP background based on STR diversity flanking the (CAG) n of ATXN3 . It was surprising to find that the Chinese MJD population originated from 8,000 to 17,000 years ago, far earlier than the previous literature reports, which will be an important evidence to explain the origin, spread and founder effects of MJD.
Aim: To identify spinocerebellar ataxia Type 3 (SCA3)-related exosomal biomarkers and the underlying mechanisms. Materials & methods: Exosomal RNAs from plasma and cerebrospinal fluid (CSF) were extracted from 24 SCA3 patients and 22 controls, respectively. Small RNA sequencing and quantitative PCR verification were performed. Gene ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the results were carried out. Results: One novel miRNA is notably downregulated in plasma-derived exosomes, while upregulated in CSF-derived exosomes of SCA3 patients. Besides, it is successively upregulated in CSF-derived exosomes from Type 1, Type 2 and Type 3 groups. The downstream target genes were enriched in protein processing in endoplasmic reticulum and axon guidance. Conclusion: One exosomal biomarker was identified in SCA3, and this is the first time to report an exosomal miRNA as a biomarker in SCA3 internationally.
microRNAs are a class of non-coding RNAs including approximately 22 nucleotides in length and play a pivotal role in post-transcriptional gene regulation. Currently, the role of miRNAs in the pathophysiology of ischemic stroke has been the subject of recent investigations. In particular, antagomirs to microRNA (miRNA) let-7f have been found to be neuroprotective in vivo, although the detailed function of let-7f during cerebral ischemia has not been fully illustrated. NDRG3 is an N-myc downstream-regulated gene (NDRG) family member that has been observed in the nuclei in most brain cells. Recently, a NDRG3-mediated lactate signaling, in which stabilized NDRG3 protein can promote angiogenesis and cell growth by activating the Raf-ERK pathway in hypoxia was discovered. In this study, we preliminarily explored the change in the expression of the NDRG3 protein which indicated that NDRG3 protein is an oxygen-regulated protein in neurons in rat cerebral ischemia in vivo and in vitro. We further identified let-7f as an upstream regulator of NDRG3 by the lentiviral transfection of rat cortical neurons and the dual luciferase analysis of human genes. In addition, a dual-color fluorescence in situ hybridization assay showed that when the expression of let-7f was elevated, the expression of NDRG3 mRNA was accordingly reduced in rat cerebral ischemia. Taken together, our results identify a new regulatory mechanism of let-7f on NDRG3 expression in the hypoxic response of cerebral ischemia and raise the possibility that the let-7f/NDRG3 pathway may serve as a potential target for the treatment of ischemic stroke.
Multiple system atrophy (MSA) is a fatal neurodegenerative disease, and the pathogenesis is still quite challenging. Emerging evidence has shown that the brain–gut–microbiota axis served a pivotal role in neurological diseases; however, researches utilizing metagenomic sequencing to analyze the alteration in gut microbiota of MSA patients were quite rare. Here, we carried out metagenomic sequencing in feces of 15 MSA patients and 15 healthy controls, to characterize the alterations in gut microbial composition and function of MSA patients in mainland China. The results showed that gut microbial community of MSA patients was significantly different from healthy controls, characterized by increased genus Akkermansia and species Roseburia hominis, Akkermansia muciniphila, Alistipes onderdonkii, Streptococcus parasanguinis, and Staphylococcus xylosus, while decreased genera Megamonas, Bifidobacterium, Blautia, and Aggregatibacter and species Bacteroides coprocola, Megamonas funiformis, Bifidobacterium pseudocatenulatum, Clostridium nexile, Bacteroides plebeius, and Granulicatella adiacens. Further, functional analysis based on the KEGG database revealed aberrant functional pathways in fecal microbiome of MSA patients. In conclusion, our findings provided evidence for dysbiosis in gut microbiota of Chinese MSA cohorts and helped develop new testable hypotheses on pathophysiology of MSA.
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