A5077883174- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Genetic Neurodegenerative Diseases
- Neurogenetic and Muscular Disorders Research
- Endoplasmic Reticulum Stress and Disease
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- Autophagy in Disease and Therapy
- Biotin and Related Studies
- Lipid metabolism and biosynthesis
- Single-cell and spatial transcriptomics
- Pancreatic function and diabetes
- Mitochondrial Function and Pathology
- Biochemical Acid Research Studies
- MicroRNA in disease regulation
- Neurological diseases and metabolism
- Cancer-related molecular mechanisms research
- Science, Research, and Medicine
- Fungal and yeast genetics research
- Pluripotent Stem Cells Research
- RNA Interference and Gene Delivery
- Molecular Biology Techniques and Applications
University of California, San Diego
2016-2022
Torrey Pines Institute For Molecular Studies
2020
The University of Melbourne
2013-2018
The Royal Melbourne Hospital
2013-2018
Ludwig Cancer Research
2014
Ludwig Cancer Research
2013
Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing expansion (GGGGCC) patient cells, including white blood fibroblasts, glia, multiple neuronal cell types (spinal motor, cortical, hippocampal, cerebellar neurons). not present sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease,...
Chronic cellular stress associated with neurodegenerative disease can result in the persistence of granule (SG) structures, membraneless organelles that form response to stress. In Huntington's (HD), chronic expression mutant huntingtin generates various forms stress, including activation unfolded protein and oxidative However, it has yet be determined whether SGs are a feature HD neuropathology. We examined miRNA composition extracellular vesicles (EVs) present cerebrospinal fluid (CSF)...
Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome translation initiation are deleterious to development underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe novel zebrafish mutant, titania (ttis450), which harbours recessive lethal mutation pwp2h, gene encoding protein component the small subunit processome. The biochemical impacts this lesion decreased production mature 18S rRNA molecules, activation Tp53, impaired...
Significance The accurate removal of introns by pre-mRNA splicing is a critical step in proper gene expression. Most eukaryotic genomes, from plant to human, contain tiny subset “minor class” with unique sequence elements that require their own machinery. significance this second pathway has intrigued RNA biologists for two decades, but its biological relevance was recently underscored when defects the process were firmly linked human disease. Here, we use novel zebrafish mutant defective...
Stress granule (SG) formation is frequently accompanied by ubiquitin proteasome system (UPS) impairment and ubiquitylated protein accumulation. SGs, ubiquitin, UPS components co-localize, but the relationship between pathway SGs has not been systematically characterized. We utilize pharmacological inhibition of either ubiquitin- or NEDD8-activating enzyme (UAE NAE) to probe whether active ubiquitylation neddylation modulate SG dynamics. show that UAE results in rapid loss global using...
Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of that underlies treatment resistance. Here we introduce a modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) captures authentic pathobiology. Orthotopic engraftment the neural progenitor derived from hiPSCs have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas...
Mutated spliceosome components are recurrently being associated with perturbed tissue development and disease pathogenesis. Cephalophŏnus ( cph ), is a zebrafish mutant carrying an early premature STOP codon in the component Prpf8 (pre‐mRNA processing factor 8). Cph initially develops normally, but then widespread cell death, especially neurons, embryonic lethal. mutants accumulate aberrantly spliced transcripts retaining both U2‐ U12‐type introns. Within haematopoiesis, myeloid...
Lipid transfer proteins mediate the exchange of lipids between closely apposed membranes at organelle contact sites and play key roles in lipid metabolism, membrane homeostasis, cellular signaling. A recently discovered novel family proteins, which includes VPS13 (VPS13A-D), adopt a rod-like bridge conformation with an extended hydrophobic groove that enables bulk for growth. Loss function mutations VPS13A VPS13C cause chorea acanthocytosis Parkinson's disease, respectively. localize to...
Splicing is an essential step in eukaryotic gene expression. While the majority of introns excised by U2-dependent, or major class, spliceosome, appropriate expression a very small subset genes depends on U12-dependent, minor splicing. The U11/U12 65K protein (hereafter 65K), encoded RNPC3 , one seven proteins that are unique to U12-dependent and previous studies including our own have established it plays role plant vertebrate development. To pinpoint impact loss during mammalian...
Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and increasingly implicated in human neurodegeneration. To study the proteome compositional diversity of SGs different cell types context neurodegeneration‐linked mutations, we used APEX proximity labeling, mass spectrometry immunofluorescence to identify ~150 previously unknown SG components. proteins a dense interaction network unstressed cells, facilitating rapid coalescence into larger...
ABSTRACT Many current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of that underlies treatment resistance. Here we introduce a new modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) capture authentic pathobiology. Orthotopic engraftment neural progenitor derived from hiPSCs have been genome-edited to contain tumor-associated genetic driver mutations revealed by The...
Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form in response to proteotoxic stress. Although SGs distinct from observed neurodegenerative disorders, they share protein components. We used APEX-mediated proximity labeling combined with quantitative mass spectrometry and high-throughput imaging identify >100 previously unknown SG proteins human cells, about 10% of which localize a cell type- or stress type-dependent manner. Supporting link between...
ABSTRACT Human genetic variants are usually represented by four values with variable length: chromosome, position, reference and alternate alleles. Thereis no guarantee that these components in a consistent way across different data sources, processing variant-based can be inefficient because comparison operations needed for each variant, three of which string comparisons. Working strings, contrast to numbers, poses extra challenges on computer memory allocation data-representation. Existing...
Stress granule (SG) formation is frequently accompanied by alterations of the ubiquitin proteasome system (UPS) and accumulation ubiquitylated proteins. Ubiquitin UPS components have been reported to co-localize with SGs, but relationship between pathway SGs has not systematically characterized. Using ubiquitin-specific proteomics we show that ~35% peptides change significantly in abundance response sodium arsenite treatment chemical inhibition ubiquitin-activating enzyme (UAE) results rapid...