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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that C9orf72 patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 (p = 0.03). Our results provide new data reinforcing that C9orf72 cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes.

Abstract Background While sex-based differences in various health scenarios have been thoroughly acknowledged in the literature, we lack sufficient tools and methods that allow for an in-depth analysis of sex as a variable in biomedical research. To fill this knowledge gap, we created MetaFun as an easy-to-use web-based tool to meta-analyze multiple transcriptomic datasets with a sex-based perspective to gain major statistical power and biological soundness. Description MetaFun is a complete suite that allows the analysis of transcriptomics data and the exploration of the results at all levels, performing single-dataset exploratory analysis, differential gene expression, gene set functional enrichment, and finally, combining results in a functional meta-analysis. Which biological processes, molecular functions or cellular components are altered in a common pattern in different transcriptomic studies when comparing male and female patients? This and other biological questions of interest can be answered with the use of MetaFun. This tool is available at https://bioinfo.cipf.es/metafun while additional help can be found at https://gitlab.com/ubb-cipf/metafunweb/-/wikis/Summary . Conclusions Overall, Metafun is the first open-access web-based tool to identify consensus biological functions across multiple transcriptomic datasets, helping to elucidate sex differences in numerous diseases. Its use will facilitate the generation of novel biological knowledge that can be used in the research and application of Personalized Medicine considering the sex of patients.

Abstract Background As the housekeeping genes (HKG) generally involved in maintaining essential cell functions are typically assumed to exhibit constant expression levels across cell types, they are commonly employed as internal controls in gene expression studies. Nevertheless, HKG may vary gene expression profile according to different variables introducing systematic errors into experimental results. Sex bias can indeed affect expression display, however, up to date, sex has not been typically considered as a biological variable. Methods In this study, we evaluate the expression profiles of six classical housekeeping genes (four metabolic: GAPDH, HPRT, PPIA, and UBC, and two ribosomal: 18S and RPL19) to determine expression stability in adipose tissues (AT) of Homo sapiens and Mus musculus and check sex bias and their overall suitability as internal controls. We also assess the expression stability of all genes included in distinct whole-transcriptome microarrays available from the Gene Expression Omnibus database to identify sex-unbiased housekeeping genes (suHKG) suitable for use as internal controls. We perform a novel computational strategy based on meta-analysis techniques to identify any sexual dimorphisms in mRNA expression stability in AT and to properly validate potential candidates. Results Just above half of the considered studies informed properly about the sex of the human samples, however, not enough female mouse samples were found to be included in this analysis. We found differences in the HKG expression stability in humans between female and male samples, with females presenting greater instability. We propose a suHKG signature including experimentally validated classical HKG like PPIA and RPL19 and novel potential markers for human AT and discarding others like the extensively used 18S gene due to a sex-based variability display in adipose tissue. Orthologs have also been assayed and proposed for mouse WAT suHKG signature. All results generated during this study are readily available by accessing an open web resource ( https://bioinfo.cipf.es/metafun-HKG ) for consultation and reuse in further studies. Conclusions This sex-based research proves that certain classical housekeeping genes fail to function adequately as controls when analyzing human adipose tissue considering sex as a variable. We confirm RPL19 and PPIA suitability as sex-unbiased human and mouse housekeeping genes derived from sex-specific expression profiles, and propose new ones such as RPS8 and UBB.

Highlights Females show a significant increase in the expression of MED31 in the frontal cortex. This gene is involved in lipid metabolism and neural diseases. We found 237 genes having sex-based significantly differential expression in substantia nigra. Functional profiling of these genes reveals a differential sex-related behavior in PD regarding their biological functions, protein-protein interaction networks, and transcription factors activation. There are remarkable sex based differential mechanisms in typical PD hallmarks: inflammation, mitochondrial dysfunction, and oxidative stress. Studies on sex differences in PD are needed to improve more targeted interventions.

The tree tomato (Solanum betaceum Cav.) is an underutilized fruit crop native to the Andean region and phylogenetically related to the tomato and potato. Tree tomato fruits have a high amount of nutrients and bioactive compounds. However, so far there are no studies at the genome or transcriptome level for this species. We performed a de novo assembly and transcriptome annotation for purple-fruited (A21) and an orange-fruited (A23) accessions. A total of 174,252 (A21) and 194,417 (A23) transcripts were assembled with an average length of 851 and 849 bp. A total of 34,636 (A21) and 36,224 (A23) transcripts showed a significant similarity to known proteins. Among the annotated unigenes, 22,096 (A21) and 23,095 (A23) were assigned to the Gene Ontology (GO) term and 14,035 (A21) and 14,540 (A23) were found to have Clusters of Orthologous Group (COG) term classifications. Furthermore, 22,096 (A21) and 23,095 (A23) transcripts were assigned to 155 and 161 (A23) KEGG pathways. The carotenoid biosynthetic process GO terms were significantly enriched in the purple-fruited accession A21. Finally, 68,647 intraspecific single-nucleotide variations (SNVs) and almost 2 million interspecific SNVs were identified. The results of this study provide a wealth of genomic data for the genetic improvement of the tree tomato.