Huntington disease (HD) is the most common neurogenetic disorder caused by expansion of the CAG repeat in the
HTT
gene; nevertheless, the molecular bases of the disease are not fully understood. ...Non-coding RNAs have demonstrated to be involved in the physiopathology of HD. However, the role of circRNAs has not been investigated. The aim of this study was to identify the circRNAs with differential expression in a murine cell line model of HD and to identify the biological pathways regulated by the differentially expressed circRNAs. CircRNA expression was analyzed through a microarray, which specifically detects circular species of RNA. The expression patterns between a murine cell line expressing mutant Huntingtin and cells expressing wild-type Huntingtin were compared. We predicted the miRNAs with binding sites for the differentially expressed circRNAs and the corresponding target genes for those miRNAs. Using the target genes, we performed a function enrichment analysis. We identified 23 circRNAs differentially expressed, 19 downregulated and four upregulated. Most of the downregulated circRNAs derive from the
Rere
gene. The dopaminergic synapse, MAPK, and long-term depression pathways were significantly enriched. The three identified pathways have been previously associated with the physiopathology of HD. The understanding of the circRNA-miRNA-mRNA network involved in the molecular mechanisms driving HD can lead us to identify novel biomarkers and potential therapeutic targets. To the best of our knowledge, this is the first study analyzing circRNAs in a model of Huntington disease.
The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim ...was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe.
This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography.
The study was completed by 104 patients. The median age was 53.3 (46.2-59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5-175.3) mg/dL at entry and 45.0 (36.0-65.0) mg/dL at follow-up (
<0.001). Coronary plaque burden changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up (
<0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%;
<0.001) and mainly fibrous (+6.2%;
<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%;
<0.001) and necrotic plaque (-0.6%;
<0.001).
Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results.
URL: https://www.
gov; Unique identifier: NCT05465278.
Obesity is considered as a strong risk factor for cardiovascular morbidity and mortality. 3D‐wall motion tracking echocardiography (3D‐WMT) provides information regarding different parameters of left ...ventricular (LV) myocardial deformation. Our aim was to assess the presence of early myocardial deformation abnormalities in nonselected obese children free from other cardiovascular risk factors. Thirty consecutive nonselected obese children and 42 healthy volunteer children were enrolled. None of them had any cardiovascular risk factor. Every subject underwent a 2D‐echo examination and a 3D‐WMT study. Mean age was 13.9 ± 2.56 and 13.25 ± 2.68 years in the nonobese and obese groups, respectively (59.7% and 40.3% male). Statistically significant differences were found for: interventricular septum thickness, LV posterior wall thickness, LV end‐diastolic volume, LV end‐systolic volume, left atrium volume, LV mass, and lateral annulus peak velocity. Regarding the results obtained by 3D‐WMT assessment, all the evaluated parameters were statistically significantly different between the two groups. When the influence of obesity on the different echocardiographic variables was evaluated by means of multivariate logistic regression analysis, the strongest relationship with obesity was found for LV average circumferential strain (β‐coefficient: 0.74; r2: 0.55; P: 0.003). Thus, obesity cardiomyopathy is associated not only with structural cardiac changes, but also with myocardial deformation changes. Furthermore, this association occurs as early as in the childhood and it is independent from any other cardiovascular risk factor. The most related parameter to obesity is LV circumferential strain.
Abstract
The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine (m
6
A) and C5 ...cytosine (m
5
C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems. Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain, give rise to different forms of disease. In this review, we discuss accumulating evidence that changes in the m
6
A and m
5
C methylation systems contribute to neurocognitive disorders. Early studies first identified mutations within
FMR1
to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m
6
A RNA reader protein. Subsequently, familial mutations within the m
6
A writer gene
METTL5
, m
5
C writer genes
NSUN2
,
NSUN3
,
NSUN5
, and
NSUN6
, as well as
THOC2
and
THOC6
that form a protein complex with the m
5
C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m
5
C writer and reader effector proteins,
NSUN6
,
NSUN7
, and
ALYREF
in brain tissue are indicated in individuals with Alzheimer’s disease, individuals with a high neuropathological load or have suffered traumatic brain injury. Likewise, an abundance of m
6
A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases, Alzheimer’s disease, and individuals with high cognitive reserve. m
6
A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson’s disease tissue, whilst modified RNAs are misplaced within diseased cells, particularly where synapses are located. In parahippocampal brain tissue, m
6
A modification is enriched in transcripts associated with psychiatric disorders including conditions with clear cognitive deficits. These findings indicate a diverse set of molecular mechanisms are influenced by RNA methylation systems that can cause neuronal and synaptic dysfunction underlying neurocognitive disorders. Targeting these RNA modification systems brings new prospects for neural regenerative therapies.
Background and purpose
Juvenile‐onset Huntington disease (JHD) is defined when symptoms initiate before 20 years of age. Mechanisms explaining differences between juvenile and adult onset are not ...fully understood. Our aim was to analyze the distribution of initial symptoms in a cohort of JHD patients and to explore its relationship with CAG expansion and relative telomere length (RTL).
Methods
A total of 84 JHD patients and 54 neurologically healthy age and sex matched individuals were recruited. CAG length was measured by southern blot or triplet repeat primed polymerase chain reaction. RTL was measured using the Cawthon method.
Results
Psychiatric symptoms were most frequent when considering the entire cohort. When divided into onset before or after 10 years, cognitive symptoms were more frequent in the youngest, whilst in the older group psychiatric symptoms prevailed. Motor symptoms were rare in the youngest and epilepsy was observed only in this group as well as a larger CAG expansion. RTL analysis revealed shorter telomeres in JHD patients compared to controls. This difference is not influenced by age, initial symptoms, time of disease or CAG expansion.
Conclusions
To the best of our knowledge this is the largest cohort of JHD patients reported. Psychiatric manifestations deserve special attention when JHD is suspected and epilepsy is especially important in the youngest patients. Initial symptoms seem to be influenced by CAG expansion and therefore age of onset. RTL is significantly reduced in JHD patients which can influence the characteristic neurodegeneration of JHD and contribute to the clinical discrepancy between adult and juvenile forms of Huntington disease.
Abstract
Background
Epigenetic processes are molecular mechanisms that contribute to the pathogenesis of neurodegenerative diseases. 5‐methylcytosine (5mC) and the oxidised state, 5‐formilcytosine ...(5fC), are known transcriptional regulators moderated by sets of writer, reader, and eraser effector proteins. We propose that gene expression variation in DNA effector proteins may contribute to Alzheimer’s Disease (AD) neuropathology. We also aimed to characterize the distribution of 5fC modifications across brain regions and within cellular compartments to better understand the role of 5mC/5fC modifications in AD.
Methods
RNA sequencing data for 17 effector proteins obtained from the Aging, Dementia and Traumatic Brain Injury Study was analysed to assess variation in abundance of 5mC writers, readers, and erasers. Gene expression data were compared across four brain regions in 51 AD and 56 healthy control samples, and between Braak and CERAD neuropathological scales. In addition, we examined the presence and distribution of 5fC by immunofluorescence (IF) across four brain regions in sections from healthy individuals.
Results
Transcripts of DNA methylation writers DNMT1, DNMT3A and DNMT3B were found increased in the AD cohort across 3 brain regions, whilst the reader UHRF1 mRNA was decreased in the same assessment. GADD45B and AICDA, DNA methylation erasers, showed changes in mRNA abundance across Braak and CERAD neuropathological load groupings. IF analysis indicated 5fC modification to be highly abundant in dentate gyrus and within the cytoplasm of hippocampal mossy cells and of neurons in cortical layer III. Within neuronal cells, we observed 5fC partially colocalizing with mitochondria especially within hippocampal neurons.
Conclusion
Our findings indicate that changes in 5mC/5hmC/5fC effector protein expression are associated with AD and its neuropathology. The characterisation of 5fC localisation in human brain indicates high abundance within the cytoplasm of hippocampal cells suggesting that 5fC may be involved in pre‐ and post‐transcriptional control of memory processing pathways and, when disrupted, may lead to neurodegenerative disease.
References
: Sanchez‐Mut JV, et al. Transl Psychiatry. 2016; Miller JA, et al. Elife. 2017; Bachman, M., et al. Nat Chem Biol. 2015; Zhang Y, Zhou C. DNA Repair (Amst). 2019; Aging, Dementia and TBI Study (2017) Available from Allen Brain Atlas
PDF
