Leslie M. Thompson
University of California, Irvine
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Publication
Featured researches published by Leslie M. Thompson.
Cell | 1993
Marcy E. MacDonald; Christine Ambrose; Mabel P. Duyao; Richard H. Myers; Carol Lin; Lakshmi Srinidhi; Glenn Barnes; Sherryl A. M. Taylor; Marianne James; Nicolet Groot; Heather MacFarlane; Barbara Jenkins; Mary Anne Anderson; Nancy S. Wexler; James F. Gusella; Gillian P. Bates; Sarah Baxendale; Holger Hummerich; Susan Kirby; Mike North; Sandra Youngman; Richard Mott; Günther Zehetner; Zdenek Sedlacek; Annemarie Poustka; Anna-Maria Frischauf; Hans Lehrach; Alan J. Buckler; Deanna Church; Lynn Doucette-Stamm
The Huntingtons disease (HD) gene has been mapped in 4p16.3 but has eluded identification. We have used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect. A new gene, IT15, isolated using cloned trapped exons from the target area contains a polymorphic trinucleotide repeat that is expanded and unstable on HD chromosomes. A (CAG)n repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4p16.3 haplotypes. The (CAG)n repeat appears to be located within the coding sequence of a predicted approximately 348 kd protein that is widely expressed but unrelated to any known gene. Thus, the HD mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
Cell | 1994
Rita Shiang; Leslie M. Thompson; Ya-Zhen Zhu; Deanna Church; Thomas J. Fielder; Maureen Bocian; Sara T. Winokur; John J. Wasmuth
Achondroplasia (ACH) is the most common genetic form of dwarfism. This disorder is inherited as an autosomal dominant trait, although the majority of cases are sporadic. A gene for ACH was recently localized to 4p16.3 by linkage analyses. The ACH candidate region includes the gene encoding fibroblast growth factor receptor 3 (FGFR3), which was originally considered as a candidate for the Huntingtons disease gene. DNA studies revealed point mutations in the FGFR3 gene in ACH heterozygotes and homozygotes. The mutation on 15 of the 16 ACH-affected chromosomes was the same, a G-->A transition, at nucleotide 1138 of the cDNA. The mutation on the only ACH-affected chromosome 4 without the G-->A transition at nucleotide 1138 had a G-->C transversion at this same position. Both mutations result in the substitution of an arginine residue for a glycine at position 380 of the mature protein, which is in the transmembrane domain of FGFR3.
Proceedings of the National Academy of Sciences of the United States of America | 2003
Emma Hockly; V M Richon; Benjamin Woodman; Donna L. Smith; X B Zhou; E Rosa; Kirupa Sathasivam; Shabnam Ghazi‐Noori; Amarbirpal Mahal; Philip A. S. Lowden; Joan S. Steffan; J L Marsh; Leslie M. Thompson; Cathryn M. Lewis; Paul A. Marks; Gillian P. Bates
Huntingtons disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease. To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood–brain barrier and increases histone acetylation in the brain. We found that SAHA could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.
Nature Reviews Drug Discovery | 2008
Aleksey G. Kazantsev; Leslie M. Thompson
Histone deacetylases (HDACs) — enzymes that affect the acetylation status of histones and other important cellular proteins — have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors — which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways — have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein–Taybi syndrome, Rett syndrome, Friedreichs ataxia, Huntingtons disease and multiple sclerosis.
Nature Genetics | 1995
Patricia L. Tavormina; Rita Shiang; Leslie M. Thompson; Ya-Zhen Zhu; Douglas J. Wilkin; Ralph S. Lachman; William R. Wilcox; David L. Rimoin; Daniel H. Cohn; John J. Wasmuth
Thanatophoric dysplasia (TD), the most common neonatal lethal skeletal dysplasia, affects one out of 20,000 live births. Affected individuals display features similar to those seen in homozygous achondroplasia. Mutations causing achondroplasia are in FGFR3, suggesting that mutations in this gene may cause TD. A sporadic mutation causing a Lys650Glu change in the tyrosine kinase domain of FGFR3 was found in 16 of 16 individuals with one type of TD. Of 39 individuals with a second type of TD, 22 had a mutation causing an Arg248Cys change and one had a Ser371 Cys substitution, both in the extracellular region of the protein. None of these mutations were found in 50 controls showing that mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder.
Cell Stem Cell | 2012
Virginia B. Mattis; Soshana Svendsen; Allison D. Ebert; Clive N. Svendsen; Alvin R. King; Malcolm Casale; Sara T. Winokur; Gayani Batugedara; Marquis P. Vawter; Peter J. Donovan; Leslie F. Lock; Leslie M. Thompson; Yu Zhu; Elisa Fossale; Ranjit S. Atwal; Tammy Gillis; Jayalakshmi S. Mysore; Jian Hong Li; Ihn Sik Seong; Yiping Shen; Xiaoli Chen; Vanessa C. Wheeler; Marcy E. MacDonald; James F. Gusella; Sergey Akimov; Nicolas Arbez; Tarja Juopperi; Tamara Ratovitski; Jason H. Chiang; Woon Roung Kim
Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, The HD Consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG-repeat-expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease-associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal, as assessed using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a human stem cell platform for screening new candidate therapeutics.
Journal of Cell Biology | 2009
Leslie M. Thompson; Charity T. Aiken; Linda S. Kaltenbach; Namita Agrawal; Ali Khoshnan; Marta Martinez-Vincente; Montserrat Arrasate; Jacqueline Gire O'Rourke; Hasan Khashwji; Tamas Lukacsovich; Ya Zhen Zhu; Alice L. Lau; Ashish C. Massey; Michael R. Hayden; Scott O. Zeitlin; Steven Finkbeiner; Kim N. Green; Frank M. LaFerla; Gillian P. Bates; Lan Huang; Paul H. Patterson; Donald C. Lo; Ana Maria Cuervo; J. Lawrence Marsh; Joan S. Steffan
The protein mutated in Huntingtons disease is phosphorylated by the inflammatory kinase IKK, which promotes other post-translational modifications, and protein degradation.
The Journal of Neuroscience | 2008
Kim N. Green; Joan S. Steffan; Hilda Martinez-Coria; Xuemin Sun; Steven S. Schreiber; Leslie M. Thompson; Frank M. LaFerla
Memory loss is the signature feature of Alzheimers disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.
Proceedings of the National Academy of Sciences of the United States of America | 2010
Ruth Luthi-Carter; David M. Taylor; Judit Pallos; Emmanuel Lambert; Allison Amore; Alex Parker; Hilary Moffitt; Donna L. Smith; Heike Runne; Ozgun Gokce; Alexandre Kuhn; Zhongmin Xiang; Michele M. Maxwell; Steven A. Reeves; Gillian P. Bates; Christian Neri; Leslie M. Thompson; J. Lawrence Marsh; Aleksey G. Kazantsev
Huntington’s disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2’s role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.
Neuron | 2009
Xiaofeng Gu; Erin R. Greiner; Rakesh Mishra; Ravindra Kodali; Alexander P. Osmand; Steven Finkbeiner; Joan S. Steffan; Leslie M. Thompson; Ronald Wetzel; X. William Yang
The N-terminal 17 amino acids of huntingtin (NT17) can be phosphorylated on serines 13 and 16; however, the significance of these modifications in Huntingtons disease pathogenesis remains unknown. In this study, we developed BAC transgenic mice expressing full-length mutant huntingtin (fl-mhtt) with serines 13 and 16 mutated to either aspartate (phosphomimetic or SD) or alanine (phosphoresistant or SA). Both mutant proteins preserve the essential function of huntingtin in rescuing knockout mouse phenotypes. However, fl-mhtt-induced disease pathogenesis, including motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration are abolished in SD but preserved in SA mice. Moreover, modification of these serines in expanded repeat huntingtin peptides modulates aggregation and amyloid fibril formation in vitro. Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in vivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy.