A5082786867- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Muscle Physiology and Disorders
- Cardiomyopathy and Myosin Studies
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
- Genetics and Neurodevelopmental Disorders
- Tribology and Lubrication Engineering
- Neurogenetic and Muscular Disorders Research
- CRISPR and Genetic Engineering
- Viral Infections and Immunology Research
- Refrigeration and Air Conditioning Technologies
- Chronic Lymphocytic Leukemia Research
- Turbomachinery Performance and Optimization
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- Adolescent and Pediatric Healthcare
- Cancer-related molecular mechanisms research
- Epigenetics and DNA Methylation
- RNA regulation and disease
University of Nevada, Las Vegas
2023-2024
Adam Mickiewicz University in Poznań
2012-2024
University of Florida
2017-2024
Florida College
2018-2023
Bridge University
2023
Shell (Netherlands)
2015
Polish Academy of Sciences
2011
Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological-neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite repeat length diversity is more prominent introns with eight different trinucleotide hexanucleotide causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal (FECD), C9orf72 amyotrophic lateral sclerosis frontotemporal dementia (C9-ALS/FTD). Here, we test the...
Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG RNAs. These mutant RNAs alter the activities RNA processing factors, including MBNL proteins, leading to re-expression fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, molecular basis congenital DM (CDM) unknown. Here, we test hypothesis that disruption developmentally regulated alternative pathways contributes CDM...
Abstract Background Numerous microRNAs (miRNAs) have heterogeneous ends resulting from imprecise cleavages by processing nucleases and various non-templated nucleotide additions. The scale of miRNA end-heterogeneity is best shown deep sequencing data revealing not only the major variants but also those that occur in minute amounts are unlikely to be functional importance. All RNA interference (RNAi) technology reagents expressed processed cells exposed same machinery generating released...
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of CTG triplet repeats in 3′-untranslated region DMPK gene. The pathomechanism DM1 driven accumulation toxic transcripts containing expanded CUG (CUGexp) nuclear foci which sequester several factors regulating RNA metabolism, such as Muscleblind-like proteins (MBNLs). In this work, we utilized very short chemically modified antisense oligonucleotides composed exclusively locked nucleic acids...
Muscleblind-like (MBNL) proteins are critical RNA processing factors in development. MBNL activity is disrupted the neuromuscular disease myotonic dystrophy type 1 (DM1), due to instability of a non-coding microsatellite DMPK gene and expression CUG expansion (CUGexp) RNAs. Pathogenic interactions between CUGexp lead formation nuclear complexes termed foci prevent function pre-mRNA processing. The existence multiple genes, as well protein isoforms, raises question whether different possess...
Recently, it was reported that expanded r(CAG) triplet repeats (r(CAG)exp) associated with untreatable neurological diseases cause pre-mRNA mis-splicing likely due to sequestration of muscleblind-like 1 (MBNL1) splicing factor. Bioactive small molecules bind the 5′CAG/3′GAC motif found in r(CAG)exp hairpin structure were identified by using RNA binding studies and virtual screening/chemical similarity searching. Specifically, a benzylguanidine-containing molecule improve alternative...
Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions (C9orf72Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. C9orf72Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immunostimulatory or damaged unknown. Here, we show in pre-symptomatic sclerosis-frontotemporal...
Muscleblind-like proteins (MBNLs) are regulators of RNA metabolism. During tissue differentiation the level MBNLs increases, while their functional insufficiency plays a crucial role in myotonic dystrophy (DM). Deep sequencing molecules cross-linked to immunoprecipitated protein particles (CLIP-seq) revealed that MBNL1 binds exon 1 (e1) encoding both major part 5΄UTR and an amino-terminal region protein. We tested several hypotheses regarding possible autoregulatory function binding its own...
Muscleblind-like (MBNL) proteins are conserved RNA-binding factors involved in alternative splicing (AS) regulation during development. While AS is controlled by distribution of MBNL paralogs and isoforms, the affinity these for specific regions their location within transcripts, it currently unclear how RNA structure impacts MBNL-mediated regulation. Here, we defined structural determinants affecting MBNL-dependent activity using both cellular biochemical assays. enhanced inclusion...
Abstract Muscleblind like splicing regulators (MBNLs) govern various RNA-processing steps, including alternative splicing, polyadenylation, RNA stability and mRNA intracellular localization. In myotonic dystrophy type 1 (DM1), the most common muscular in adults, MBNLs are sequestered on toxic containing expanded CUG repeats, which leads to disruption of MBNL-regulated processes disease features DM1. Herein, we show significance regulating microtranscriptome dynamics during postnatal...
Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models recapitulate the tissue specificity developmental timing of an STR gene, we used rolling circle amplification CRISPR/Cas9-mediated genome editing generate Dmpk CTG (CTG exp ) knockin myotonic dystrophy type 1 (DM1). We demonstrate skeletal muscle myoblasts brain choroid plexus epithelial cells particularly susceptible...
Abstract The thymus is a primary lymphoid organ that plays an essential role in T lymphocyte maturation and selection during development of one arm the mammalian adaptive immune response. Although transcriptional mechanisms have been well documented thymocyte development, co-/post-transcriptional modifications are also important but received less attention. Here we demonstrate RNA alternative splicing factor MBNL1, which sequestered nuclear foci by C(C)UG microsatellite expansions myotonic...
Abstract The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72, is linked to multiple diseases. C9orf72 (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked immune DNA damage responses, but source of immuno-stimulatory or damaged unknown. Here, we show in pre-symptomatic ALS-FTD patient cells brains cause...
Alternative splicing is a complex process that provides high diversity of proteins from limited number protein-coding genes. It governed by multiple regulatory factors, including RNA-binding (RBPs), bind to specific RNA sequences embedded in structure. The ability predict regions recognized RBPs using whole-transcriptome approaches can deliver multitude data, false-positive hits. Therefore, validation the global results indispensable. Here, we report development an efficient and rapid...
Abstract Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3′ untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester inhibit activities of MBNL family developmental RNA processing factors. Although myotonic classified as muscular dystrophy, brain also severely affected an unusual cohort symptoms, including hypersomnia, executive dysfunction, well early onsets tau/MAPT...
Shell Global Solutions uses an in-house developed system for remote condition monitoring of centrifugal compressors. It requires field process data collected during operation to calculate and assess the machine's performance. Performance is assessed by comparing live results polytropic head efficiency versus design compressor curves provided Manufacturer. Typically, these are given specific suction conditions. The further conditions on site deviate from those prescribed at design, less...
Abstract Muscleblind-like splicing regulators (MBNLs) activate or repress the inclusion of alternative (AS) events, enabling developmental transition fetal mRNA isoforms to their adult forms. Herein, we sought elaborate mechanism by which MBNLs mediate AS related biological processes. We evaluated functional role DEAD-box (DDX) RNA helicases, DDX5 and DDX17 in MBNL-dependent regulation. Whole-transcriptome analysis validation approaches revealed a handful MBNLs-dependent events be affected...
<title>Abstract</title> Tandem repeat expansions are enriched in autism spectrum disorder, including CTG expansion the DMPK gene that underlines myotonic muscular dystrophy type 1. Although clinical connection of to is corroborated, molecular links remained unknown. Here, we show a mechanistic path via dystrophy. We found inhibition muscleblind-like (MBNL) splicing factors by expanded CUG RNAs alerts autism-risk genes during brain development especially class autism-relevant microexons. To...
ABSTRACT Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM disease presentation highly variable and distinguished differences age‐of‐onset symptom severity. In the most severe form, presents with congenital onset profound developmental defects. At molecular level, pathogenesis characterized toxic RNA gain‐of‐function mechanism that involves transcription of noncoding...