MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease

Maier, Nadine; Gatterer, Constantin; Haider, Patrick; Salzmann, Manuel; Kaun, Christoph; Speidl, Walter S.; Sunder‐Plassmann, Gere; Podesser, Bruno K.; Wojta, Johann; Graf, Senta; Lenz, Max; Hohensinner, Philipp J.

doi:10.3390/genes12081184

Cited by 5 publications

(4 citation statements)

References 21 publications

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“…Alterations in over 100 circulating miRNAs were identified in blood samples from FD patients in treatment with ERT compared with untreated patients (Xiao et al, 2019). Increased expression of miRNA miR-29a-3p and miR-200a-3p were detected in urinary extracellular vesicles isolated from patients with FD nephropathy (Levstek et al, 2021) which associates with the progression of kidney damage (Maier et al, 2021); miR-let-7a and let-7d were significantly increased in FD after therapy and have been suggested as potential markers for enzyme activity and inflammation in FD patients (Maier et al, 2021). These data point at miRNA profiling as a powerful diagnostic tool of FD progression and drug testing, as well as indicators of the development of specific FD phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease

Gambardella

Fiordelisi

Sorriento

et al. 2022

J Pharmacol Exp Ther

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We demonstrate for the first time that a specific signature of circulating mitochondrial microRNAs (mitomiRs) is dysregulated in Fabry disease (FD). In our study, we observed that mitomiRs regulating fundamental aspects of mitochondrial homeostasis and fitness, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, our new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease

Gambardella

Fiordelisi

Sorriento

et al. 2022

J Pharmacol Exp Ther

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“…At a cellular level, GB3 accumulation has been linked to inflammation, ROS production, NFκB activation, leading to cell death as well as sclerosis, fibrosis, etc. ( 6 – 9 ). GB3 accumulation has also been observed in the testis ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Sansone,

Barreca,

Belli

et al. 2024

Front. Endocrinol.

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IntroductionFabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease characterized by the accumulation of globotriaosylceramide (GB3) into the lysosomes of many tissues. FD is due to loss-of-function mutations of α-galactosidase, a key-enzyme for lysosomal catabolism of glycosphingolipids, which accumulate as glycolipid bodies (GB). In homozygous males the progressive deposition of GB3 into the cells leads to clinical symptoms in CNS, skin, kidney, etc. In testis GB accumulation causes infertility and alterations of spermatogenesis. However, the precise damaging mechanism is still unknown. Our hypothesis is that GB accumulation reduces blood vessel lumen and increases the distance of vessels from both stromal cells and seminiferous parenchyma; this, in turn, impairs oxygen and nutrients diffusion leading to subcellular degradation of seminiferous epithelium and sterility.MethodsTo test this hypothesis, we have studied a 42-year-old patient presenting a severe FD and infertility, with reduced number of spermatozoa, but preserved sexual activity. Testicular biopsies were analyzed by optical (OM) and transmission electron microscopy (TEM). Activation and cellular localization of HIF-1α and NFκB was analyzed by immunofluorescence (IF) and RT-PCR on homogeneous tissue fractions after laser capture microdissection (LCMD).ResultsOM and TEM showed that GB were abundant in vessel wall cells and in interstitial cells. By contrast, GB were absent in seminiferous epithelium, Sertoli’s and Leydig’s cells. However, seminiferous tubular epithelium and Sertoli’s cells showed reduced diameter, thickening of basement membrane and tunica propria, and swollen or degenerated spermatogonia. IF showed an accumulation of HIF-1α in stromal cells but not in seminiferous tubules. On the contrary, NFκB fluorescence was evident in tubules, but very low in interstitial cells. Finally, RT-PCR analysis on LCMD fractions showed the expression of pro-inflammatory genes connected to the HIF-1α/NFκB inflammatory-like pathway.ConclusionOur study demonstrates that infertility in FD may be caused by reduced oxygen and nutrients due to GB accumulation in blood vessels cells. Reduced oxygen and nutrients alter HIF-1α/NFκB expression and localization while activating HIF-1α/NFκB driven-inflammation-like response damaging seminiferous tubular epithelium and Sertoli’s cells.

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“… 23 , 24 Additionally, miR-184, let-7a, and let-7d have been reported to be beneficial in diagnosing and treating Fabry disease, a hereditary cerebral small vessel disease. 25 , 26 Nevertheless, the study of circulating exosomal miRNAs in CSVD is still in its infancy. In the few studies published so far, exosomal miRNA-17 family and miR-223-3p were proved to be closely related to the initiation and development of CSVD.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease

Gao¹,

Yin²,

Wang³

et al. 2023

IJGM

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Background Cerebral small vessel disease (CSVD) with an insidious onset can cause overall neurological dysfunction and dementia, bringing a massive burden to society. However, the pathogenesis of CSVD is complex and reliable non-invasive biomarkers for diagnosis are still not available at present. Our study aimed to investigate abnormal exosomal miRNA patterns via microarray analysis and identify candidate biomarkers for CSVD. Methods We isolated exosomes from the plasma of all subjects and identified exosomes via currently universally accepted methods. The miRNAs were profiled through microarrays, and then the expression of selected differentially expressed miRNAs was validated through RT-PCR. GO and KEGG analysis predicted possible functions of differentially expressed miRNAs. Receiver operating characteristic (ROC) curve was employed to observe the diagnostic value of selective miRNAs. Finally, the relationship between the expression of miR-320e and the CSVD burden was analyzed. Results A total of 14 miRNAs displayed differential enrichment levels with |fold change|≥1.5 and p<0.05 through miRNA microarray analysis. The RT-PCR analysis validated that exosomal miR-320e was significantly downregulated in CSVD patients (p<0.0001). ROC curve analysis of exosomal miR-320e showed the area under the curve of 0.752. According to the multivariable analysis, miR-320e was an independent predictor of white matter hyperintensity ([aOR]= 0.452, 95% confidence interval [CI]= 0.258–0.792, p=0.006) and exhibited a negative correlation with the load of periventricular white matter hyperintensities (p=0.0021) and deep white matter hyperintensities (p=0.0018), respectively. In addition, it exhibited a negative correlation with total CSVD burden score (r=−0.276, p=0.001). Conclusion In our study, plasma exosomal miR-320e has a certain diagnostic value for CSVD, and a significant correlation with imaging burden of CSVD. Overall, exosomal miR-320e has the potential to be a novel biomarker for CSVD, but further research with a large sample size is necessary to assess its clinical utility.

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MiRNA Let-7a and Let-7d Are Induced by Globotriaosylceramide via NF-kB Activation in Fabry Disease

Cited by 5 publications

References 21 publications

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease

Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease

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