Molecules, Vol. 25, Pages 525: Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD

Molecules, Vol. 25, Pages 525: Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD Molecules doi: 10.3390/molecules25030525 Authors: Božič Zalar Rogelj Plavec Šket The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K+ ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotid...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research

Related Links:

We studied the expression ofC9orf72 gene in pathologies associated with hexanucleotide repeats expansion in this gene: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The study included 7 patients with hexanucleotide repeats expansion in theC9orf72 gene and 9 patients of the control group. The expression ofC9orf72 mRNA was evaluated in blood leukocytes by real-time PCR. Methylation of CpG-sites inC9orf72 promotor region was evaluated by DNA sequencing after bisulfite conversion. A 2-fold decrease in theC9orf72 gene expression was found in patients with hexanucleotide repeats expansion in comparison w...
Source: Bulletin of Experimental Biology and Medicine - Category: Biology Source Type: research
Disrupting pathogenic variants in RNA-binding proteins such as TDP-43, hnRNPA2B1, FUS, TIA-1 are known to cause a spectrum of diseases, including frontotemporal dementia, amyotrophic lateral sclerosis, inclusion body myopathy, and/or distal myopathy. Using deep clinical phenotyping and exome sequencing, we identified six unrelated families all with a distinct class of dominantly-acting heterozygous variants in hnRNPA2B1 with a unique clinical phenotype of early childhood-onset progressive muscle weakness, ophthalmoplegia, ptosis, dysphagia, and variable degrees of respiratory insufficiency but no dementia.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative conditions with shared genetic susceptibility and a large portion of familial cases due to c9orf72 gene mutations. Brain imaging studies in asymptomatic c9orf72 carriers have demonstrated white (WM) and grey matter (GM) degeneration before the age of 40. The aim of this study was to investigate whether cervical spinal cord (SC) degeneration can be detected in asymptomatic c9orf72 hexanucleotide carriers using multimodal quantitative imaging.
Source: Neuromuscular Disorders - Category: Neurology Authors: Source Type: research
Conclusions: The caregivers of patients with cancer or chronic severe illnesses experience high levels of fatigue: the longer the disease duration, the greater the degrees of depression, anxiety, and physical fatigue experienced by the caregivers. Such caregivers need strategies to manage their fatigue and depression. PMID: 32963657 [PubMed - in process]
Source: Pain Research and Management - Category: Anesthesiology Authors: Tags: Pain Res Manag Source Type: research
da CA Abstract Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research
Abstract In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pat...
Source: Ageing Research Reviews - Category: Genetics & Stem Cells Authors: Tags: Ageing Res Rev Source Type: research
We appreciate the criticism raised by Dr. Matsuura questioning the genetic evaluation for NOP56 gene of Asidan (spinocerebellar ataxia 36) showing clinical anticipation. Asidan is an autosomal dominant neurodegenerative disorder caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene, showing cerebellar ataxia, motor neuron disease phenotype, hearing loss and frontal cognitive impairment [1 –3]. The NOP56 genetic mutation in Asidan is similar to the hexanucleotide GGGGCC repeat expansion in intron 1 of the C9orf72 gene observed in familial amyotrophic lateral sclerosis/frontotemporal dementia...
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
Abstract Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar pr...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
(University of Pennsylvania School of Medicine) An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein's buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic. Results were published in Science Translational Medicine.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
Repeat expansion mutations in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG translation of this expansion produces dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR and polyPR, are consistently reported to be the most toxic. Here we demonstrated that small molecule inhibition of type I protein arginine methyltransferases (PRMT) protects against polyGR and polyPR toxicity. Furthermore, our findings suggest that asymmetric dimethylation of polyGR and polyPR by Type I PRMTs plays important roles in their cytotoxicity.
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
More News: ALS | Brain | Chemistry | Dementia | Genetics | Neurology | Toxicology