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Julia A. Kaye

Bio: Julia A. Kaye is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Induced pluripotent stem cell & Huntington's disease. The author has an hindex of 14, co-authored 21 publications receiving 1645 citations. Previous affiliations of Julia A. Kaye include Gladstone Institutes & University of California, Davis.

Papers
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Journal ArticleDOI
Aude Nicolas1, Kevin P. Kenna2, Alan E. Renton1, Alan E. Renton3  +432 moreInstitutions (78)
21 Mar 2018-Neuron
TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.

444 citations

Journal ArticleDOI
TL;DR: The generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls reveal CAG-repeat-expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD.

429 citations

Journal ArticleDOI
Alexandra B Keenan1, Sherry L. Jenkins1, Kathleen M. Jagodnik1, Simon Koplev1, Edward He1, Denis Torre1, Zichen Wang1, Anders B. Dohlman1, Moshe C. Silverstein1, Alexander Lachmann1, Maxim V. Kuleshov1, Avi Ma'ayan1, Vasileios Stathias2, Raymond Terryn2, Daniel J. Cooper2, Michele Forlin2, Amar Koleti2, Dusica Vidovic2, Caty Chung2, Stephan C. Schürer2, Jouzas Vasiliauskas3, Marcin Pilarczyk3, Behrouz Shamsaei3, Mehdi Fazel3, Yan Ren3, Wen Niu3, Nicholas A. Clark3, Shana White3, Naim Al Mahi3, Lixia Zhang3, Michal Kouril3, John F. Reichard3, Siva Sivaganesan3, Mario Medvedovic3, Jaroslaw Meller3, Rick J. Koch1, Marc R. Birtwistle1, Ravi Iyengar1, Eric A. Sobie1, Evren U. Azeloglu1, Julia A. Kaye4, Jeannette Osterloh4, Kelly Haston4, Jaslin Kalra4, Steve Finkbiener4, Jonathan Z. Li5, Pamela Milani5, Miriam Adam5, Renan Escalante-Chong5, Karen Sachs5, Alexander LeNail5, Divya Ramamoorthy5, Ernest Fraenkel5, Gavin Daigle6, Uzma Hussain6, Alyssa Coye6, Jeffrey D. Rothstein6, Dhruv Sareen7, Loren Ornelas7, Maria G. Banuelos7, Berhan Mandefro7, Ritchie Ho7, Clive N. Svendsen7, Ryan G. Lim8, Jennifer Stocksdale8, Malcolm Casale8, Terri G. Thompson8, Jie Wu8, Leslie M. Thompson8, Victoria Dardov7, Vidya Venkatraman7, Andrea Matlock7, Jennifer E. Van Eyk7, Jacob D. Jaffe9, Malvina Papanastasiou9, Aravind Subramanian9, Todd R. Golub, Sean D. Erickson10, Mohammad Fallahi-Sichani10, Marc Hafner10, Nathanael S. Gray10, Jia-Ren Lin10, Caitlin E. Mills10, Jeremy L. Muhlich10, Mario Niepel10, Caroline E. Shamu10, Elizabeth H. Williams10, David Wrobel10, Peter K. Sorger10, Laura M. Heiser11, Joe W. Gray11, James E. Korkola11, Gordon B. Mills12, Mark A. LaBarge13, Mark A. LaBarge14, Heidi S. Feiler11, Mark A. Dane11, Elmar Bucher11, Michel Nederlof11, Damir Sudar11, Sean M. Gross11, David Kilburn11, Rebecca Smith11, Kaylyn Devlin11, Ron Margolis, Leslie Derr, Albert Lee, Ajay Pillai 
TL;DR: The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders.
Abstract: The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.

300 citations

Journal ArticleDOI
TL;DR: Two related phenomena are suggested: an intrachromosomal association that holds the halves of a single broken sister chromatid together in metaphase and an interchromosomal force that tethers broken sister Chromatids to each other and promotes their missegregation.

163 citations

Journal ArticleDOI
TL;DR: The data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice.
Abstract: Neural cultures derived from Huntington’s disease (HD) patient-derived induced pluripotent stem cells were used for ‘omics’ analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.

162 citations


Cited by
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Journal ArticleDOI
TL;DR: Current models of the mechanisms that cause copy number variation focus on perturbation of DNA replication and replication of non-contiguous DNA segments and cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
Abstract: Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans Here we review current models of the mechanisms that cause copy number variation Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change

1,169 citations

Journal ArticleDOI
TL;DR: A new dedicated aspect of BioGRID annotates genome-wide CRISPR/Cas9-based screens that report gene–phenotype and gene–gene relationships, and captures chemical interaction data, including chemical–protein interactions for human drug targets drawn from the DrugBank database and manually curated bioactive compounds reported in the literature.
Abstract: The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the curation and archival storage of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2018 (build 3.4.164), BioGRID contains records for 1 598 688 biological interactions manually annotated from 55 809 publications for 71 species, as classified by an updated set of controlled vocabularies for experimental detection methods. BioGRID also houses records for >700 000 post-translational modification sites. BioGRID now captures chemical interaction data, including chemical-protein interactions for human drug targets drawn from the DrugBank database and manually curated bioactive compounds reported in the literature. A new dedicated aspect of BioGRID annotates genome-wide CRISPR/Cas9-based screens that report gene-phenotype and gene-gene relationships. An extension of the BioGRID resource called the Open Repository for CRISPR Screens (ORCS) database (https://orcs.thebiogrid.org) currently contains over 500 genome-wide screens carried out in human or mouse cell lines. All data in BioGRID is made freely available without restriction, is directly downloadable in standard formats and can be readily incorporated into existing applications via our web service platforms. BioGRID data are also freely distributed through partner model organism databases and meta-databases.

1,046 citations

Journal ArticleDOI
TL;DR: The enzymology of the process is discussed, followed by studies on DSB repair in living cells, and a historical context for the current view of HR is provided and how DSBs are processed during HR as well as interactions with other D SB repair pathways are described.
Abstract: In this review, we discuss the repair of DNA double-strand breaks (DSBs) using a homologous DNA sequence (i.e., homologous recombination [HR]), focusing mainly on yeast and mammals. We provide a historical context for the current view of HR and describe how DSBs are processed during HR as well as interactions with other DSB repair pathways. We discuss the enzymology of the process, followed by studies on DSB repair in living cells. Whenever possible, we cite both original articles and reviews to aid the reader for further studies.

731 citations

Journal ArticleDOI
TL;DR: Findings support the idea that the buildup of “toxic” RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS, and suggest that antisense oligonucleotides targeting this transcript may be a strategy for treating ALS patients with the C9ORF72 repeat expansion.
Abstract: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative condition characterized by loss of motor neurons in the brain andspinalcord.Expansionsofahexanucleotide repeat(GGGGCC) in thenoncodingregionoftheC9ORF72geneare the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases. How the repeat expansion causes disease remains unclear, with both loss of function (haploinsufficiency) and gain of function (either toxic RNA or protein products) proposed. We report a cellular model of C9-ALS with motor neurons differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying the C9ORF72 repeat expansion. No significant loss of C9ORF72 expression was observed, and knockdown of the transcript was not toxic to cultured human motor neurons. Transcription of the repeat was increased, leading to accumulation of GGGGCC repeat–containing RNA foci selectively in C9-ALS iPSC-derived motor neurons. Repeat-containing RNA foci colocalized with hnRNPA1 andPur-a, suggestingthat they maybe ableto alter RNAmetabolism. C9-ALSmotor neurons showed altered expression of genes involved in membrane excitability including DPP6, and demonstrated a diminished capacity to fire continuous spikes upon depolarization compared to control motor neurons. Antisense oligonucleotides targeting the C9ORF72 transcript suppressed RNA foci formation and reversed gene expression alterations in C9-ALS motorneurons.Thesedatashowthatpatient-derivedmotorneuronscanbeusedtodelineatepathogeniceventsinALS.

611 citations

Journal ArticleDOI
TL;DR: Following DNA repair, the checkpoint pathway is inactivated in a process termed recovery, and a related but genetically distinct process, adaptation, controls cell cycle re-entry in the face of unrepairable damage.
Abstract: In response to even a single chromosomal double-strand DNA break, cells enact the DNA damage checkpoint. This checkpoint triggers cell cycle arrest, providing time for the cell to repair damaged chromosomes before entering mitosis. This mechanism helps prevent the segregation of damaged or mutated chromosomes and thus promotes genomic stability. Recent work has elucidated the molecular mechanisms underlying several critical steps in checkpoint activation, notably the recruitment of the upstream checkpoint kinases of the ATM and ATR families to different damaged DNA structures and the molecular events through which these kinases activate their effectors. Chromatin modification has emerged as one important component of checkpoint activation and maintenance. Following DNA repair, the checkpoint pathway is inactivated in a process termed recovery. A related but genetically distinct process, adaptation, controls cell cycle re-entry in the face of unrepairable damage.

567 citations