A5012545482- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Genetic Neurodegenerative Diseases
- DNA and Nucleic Acid Chemistry
- Parkinson's Disease Mechanisms and Treatments
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- Bacterial Genetics and Biotechnology
- RNA and protein synthesis mechanisms
- Nerve injury and regeneration
- Mitochondrial Function and Pathology
- Prion Diseases and Protein Misfolding
- RNA Interference and Gene Delivery
- Receptor Mechanisms and Signaling
- Cancer therapeutics and mechanisms
- RNA modifications and cancer
- Biochemical Acid Research Studies
- Biopolymer Synthesis and Applications
- Genetics and Neurodevelopmental Disorders
- Neurological diseases and metabolism
- biodegradable polymer synthesis and properties
- Educational Robotics and Engineering
- Genomics and Chromatin Dynamics
- Neuroscience and Neuropharmacology Research
- Enterobacteriaceae and Cronobacter Research
Thomas Jefferson University
2019-2025
Jefferson Hospital for Neuroscience
2019-2023
Johns Hopkins University
2013-2020
Johns Hopkins Medicine
2020
University of Baltimore
2015
Indiana University School of Medicine
2015
University of Maryland, College Park
2009-2013
University of Michigan
2012
Research Article7 January 2019Open Access Source Data Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress Thomas Westergard Department of Neuroscience, Jefferson Weinberg ALS Center, Vickie Jack Farber Institute for University, Philadelphia, PA, USA Search more papers this author Kevin McAvoy Katelyn Russell Xinmei Wen Yu Pang Brandie Morris Piera Pasinelli Davide Trotti Corresponding Author [email protected] orcid.org/0000-0001-6338-6404...
The long non-coding RNA NEAT1 serves as a scaffold for the assembly of paraspeckles, membraneless nuclear organelles involved in gene regulation. Paraspeckle requires recruitment RNA-binding protein NONO, however elements responsible are unknown. Herein we present evidence that previously unrecognized structural features serve an important role these interactions. Led by initial observation NONO preferentially binds G-quadruplex conformation G-rich C9orf72 repeat RNA, find motifs abundant...
A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion C9ORF72 gene and its relevance frontotemporal dementia (FTD) amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this was to connect basic scientists, clinical researchers, drug developers, individuals affected by C9ORF72-FTD/ALS evaluate how collaborative efforts across FTD-ALS disease spectrum might break down existing silos. Presentations discussions covered recent...
Article29 April 2020Open Access Source DataTransparent process Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued SV2 replenishment Brigid K Jensen orcid.org/0000-0003-1624-6307 Jefferson Weinberg ALS Center, Department of Neuroscience, Vickie and Jack Farber Institute for Thomas University, Philadelphia, PA, USA Search more papers this author Martin H Schuldi German Center Neurodegenerative Diseases (DZNE), Munich, Germany Kevin McAvoy Katelyn A Russell...
The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)
The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9orf72 (C9) gene is most common cause of ALS and FTD. Neuronal activity plays an essential role shaping biological processes within both healthy neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE iPSC-cortical neurons display aberrations several pathways, including synaptic signaling transcriptional machinery, potentially priming diseased for altered response to neuronal stimulation. Indeed,...
Abstract Translation of the hexanucleotide G4C2 expansion associated with C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about contribution a single DPR disease pathogenesis. We show here short length sufficient for poly-GR neurotoxicity in vitro, phenomenon previously unobserved. This toxicity also reported vivo our novel knock-in mouse model...
Abstract Expanded intronic G 4 C 2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone neurotoxic. Here, we report that Kapβ2 GR interact, co-aggregating, cultured neurons in-vitro CNS tissue in-vivo. Importantly, this interaction significantly decreased risk of...
Abstract Genetic mutations that cause amyotrophic lateral sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within neurons, growing evidence suggests dysfunction of non‐neuronal cells is also an important driver disease. Previously, we demonstrated DNA/RNA binding protein fused sarcoma (FUS) induce neurotoxic phenotypes astrocytes vitro , via activation the NF‐κB pathway and release pro‐inflammatory...
DNA looping mediated by the Lac repressor is an archetypal test case for modeling protein and flexibility. Understanding fundamental to quantitative descriptions of gene expression. Systematic analysis LacI•DNA was carried out using a landscape constructs with lac operators bracketing A-tract bend, produced varying helical phasings between bend. Fluorophores positioned on either side both allowed direct Förster resonance energy transfer (FRET) detection parallel (P1) antiparallel (A1, A2)...
The E. coli Lac repressor (LacI) tetramer binds simultaneously to a promoter-proximal DNA binding site (operator) and an auxiliary operator, resulting in loop, which increases repression efficiency. Induction of the lac operon by allolactose reduces affinity LacI for DNA, but induction does not completely prevent looping vivo. Our previous work on conformations loops used hyperstable model construct, 9C14, that contains sequence directed bend flanked operators. Single-molecule fluorescence...
Abstract A nucleotide repeat expansion (NRE), (G 4 C 2 ) n , located in a classically noncoding region of C9orf72 (C9), is the most common genetic mutation associated with ALS/FTD. There increasing evidence that nucleic acid structures formed by C9-NRE may both contribute to ALS/FTD, and serve as therapeutic targets, but there limited characterization these under physiologically disease relevant conditions. Here we show vitro DNA can form parallel antiparallel G-quadruplex (GQ) topological...
Abstract Translation of the hexanucleotide G4C2 expansion associated with C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD) produces five different dipeptide repeat protein (DPR) species that can confer toxicity. There is yet much to learn about contribution a single DPR disease pathogenesis. We show here short length sufficient for poly-GR neurotoxicity in vitro, phenomenon previously unobserved. This toxicity also reported vivo our novel knock-in mouse model...
A nucleotide repeat expansion (NRE) mutation, (G4C2)n, in a non-coding region of the C9orf72 gene locus, is most common genetic cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The biological functions are becoming increasingly clear, but it unknown whether this can be regulated neural-specific manner. Neuronal activity crucial modifier processes health neurodegenerative disease contexts. Here, we show that prolonged membrane depolarization human iPSC-derived...
The (G4C2)n nucleotide repeat expansion (NRE) mutation in C9orf72 is the most common genetic cause of ALS and FTD. biological functions are becoming understood, but it unclear if this gene regulated a neural-specific manner. Neuronal activity crucial modifier processes health neurodegenerative disease contexts. Here, we show that prolonged membrane depolarization healthy human iPSC-cortical neurons leads to significant downregulation transcript variant 3 (V3) C9orf72, with concomitant...
The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)