A5067520285- Glioma Diagnosis and Treatment
- Amyotrophic Lateral Sclerosis Research
- Cancer Cells and Metastasis
- Cancer-related molecular mechanisms research
- Neurogenetic and Muscular Disorders Research
- Anorectal Disease Treatments and Outcomes
- Mitochondrial Function and Pathology
- Lipid metabolism and biosynthesis
- Pelvic and Acetabular Injuries
- Pelvic floor disorders treatments
- Genetics and Neurodevelopmental Disorders
- Alzheimer's disease research and treatments
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Meningioma and schwannoma management
- Nuclear Structure and Function
- Sleep and Wakefulness Research
- Angiogenesis and VEGF in Cancer
- Lymphatic System and Diseases
- Ferroptosis and cancer prognosis
- Circular RNAs in diseases
- Fungal and yeast genetics research
- Neurobiology and Insect Physiology Research
- Genetics, Aging, and Longevity in Model Organisms
- Prion Diseases and Protein Misfolding
Baylor College of Medicine
2015-2025
Texas Children's Hospital
2021-2024
Neurological Research Institute
2019-2024
University of Pennsylvania
2014-2023
The University of Texas MD Anderson Cancer Center
2009-2018
Significance Multiple studies have implicated dozens of risk loci that may be associated with Alzheimer’s disease (AD), but common mechanisms underlying how they contribute to onset or progression remain elusive. This study identifies cell-specific roles for Drosophila orthologs AD genes in lipid droplet formation that, when disrupted, lead neurodegeneration. Our work reinforces a critical role the sequestration peroxidated lipids glia, and places Apolipoprotein E ε4 (APOE4) other factors...
An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the sequence (GGGGCC); however, this approach is complicated by presence of antisense strand transcription GGCCCC repeats. We found that targeting elongation factor Spt4 selectively decreased production both sense transcripts, as well their translated dipeptide (DPR) products, also mitigated degeneration animal...
Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal in human gliomas glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized a higher percentage of tumors predicts poor patient prognosis.We determined the coexpressing GA-hMSC markers CD105+/CD73+/CD90+ from patients with newly diagnosed high-grade glioma analyzed association between this...
During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role several neurodegenerative diseases. Yet, the mechanisms of lipid and its consequences on neuronal health unclear. Here, we demonstrate lipid-protein particle autolysosome exocytosis protects from ferroptosis, a form cell death driven peroxidation. We show during stress, peroxidated iron released autolysosomal which requires exocytic machinery VAMP7 syntaxin...
The discovery of an expanded (GGGGCC)n repeat (termed G4C2) within the first intron C9orf72 in familial ALS/FTD has led to a number studies showing that aberrant expression G4C2 RNA can produce toxic dipeptides through repeat-associated non-AUG (RAN-) translation. To reveal canonical translation factors impact this process, unbiased loss-of-function screen was performed fly model maintained upstream intronic sequence human gene and contained GFP tag GR reading frame. 11 48 were identified...
Abstract Peripheral tissues become disrupted in Alzheimer’s Disease (AD). However, a comprehensive understanding of how the expression AD-associated toxic proteins, Aβ42 and Tau, neurons impacts periphery is lacking. Using Drosophila , prime model organism for studying aging neurodegeneration, we generated Fly Cell Atlas (AD-FCA): whole-organism single-nucleus transcriptomes 219 cell types from adult flies neuronally expressing human or Tau. In-depth analyses functional data reveal on...
// Adriana Olar 1 , Lindsey D. Goodman 2 Khalida M. Wani 3 Nicholas S. Boehling 4 Devi Sharma 5 Reema R. Mody Joy Gumin 6 Elizabeth B. Claus 7, 8 Frederick F. Lang Timothy Cloughesy Albert Lai Kenneth Aldape 9 Franco DeMonte and Erik P. Sulman 3, 10 Medical University of South Carolina & Hollings Cancer Center, Departments Pathology Laboratory Medicine Neurosurgery, Charleston, SC, USA Neurosciences Graduate Group, Perlman School Medicine, Pennsylvania, Department Biology, Philadelphia, PA,...
A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of gene product has been proposed as a potential disease pathogenesis. Additionally, repetitive RNAs dipeptide proteins (DPRs), such poly-GR, can be produced by this that disrupt number cellular processes, potentially contributing neural degeneration. To better discern which these mechanisms leads...
Background Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene silenced. However, even responsive cases, its beneficial effect undermined by emergence of drug resistance. Here, we tested whether inhibition poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced effectiveness TMZ. Methods Using patient derived brain tumor initiating cells (BTICs) orthotopic xenografts as models newly diagnosed recurrent high-grade glioma,...
RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact TDP-43, we found downregulation of mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, depletion also reduced toxicity caused by expression C9orf72 GGGGCC repeat expansion. knockdown lowered levels these...
Summary Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora risk loci. However, the variants/genes and underlying mechanisms remain largely unknown. For strong AD-associated locus near Clusterin ( CLU ), we tied an AD protective allele to role neuronal in promoting neuron excitability through lipid-mediated neuron-glia communication. We putative causal SNP that impacts neuron-specific chromatin accessibility transcription-factor(s), with upregulating...
Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) 2 (DM2), respectively. A gain-of-function these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 resultant loss activity proteins. To study mechanisms CCUG-repeat an animal model, we created a fly model DM2 that expresses pure, uninterrupted ranging from 16 to 720 length. We show this...
Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers our ability target them specifically not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple patient cohorts comprising both high- low-grade gliomas. Knockdown PDPN radiosensitized cell lines glioma-stem-like (GSCs). Clonogenic assays xenograft experiments revealed was associated with radiotherapy...