Taube Koret Center for Huntingtons Disease Research

San Francisco, CA, United States

Taube Koret Center for Huntingtons Disease Research

San Francisco, CA, United States
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Bouchard J.,University of California at San Francisco | Bouchard J.,Gladstone | Truong J.,Gladstone | Bouchard K.,University of California at San Francisco | And 10 more authors.
Journal of Neuroscience | Year: 2012

Peripheral immune cells and brain microglia exhibit an activated phenotype in premanifest Huntington's disease (HD) patients that persists chronically and correlates with clinical measures of neurodegeneration. However, whether activation of the immune system contributes to neurodegeneration in HD, or is a consequence thereof, remains unclear. Signaling through cannabinoid receptor 2 (CB2) dampens immune activation. Here, we show that the genetic deletion of CB2 receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB2 receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB2 receptor antagonist blocks these effects. CB2 receptors regulate blood interleukin-6 (IL-6) levels, and IL-6 neutralizing antibodies partially rescue motor deficits and weight loss inHDmice. These findings support a causal link between CB2 receptor signaling in peripheral immune cells and the onset and severity of neurodegeneration in HD, and they provide a novel therapeutic approach to treat HD. © 2012 the authors.

Margulis J.,Gladstone | Margulis J.,University of California at San Francisco | Finkbeiner S.,Gladstone | Finkbeiner S.,University of California at San Francisco | Finkbeiner S.,Taube Koret Center for Huntingtons Disease Research
Frontiers in Cellular Neuroscience | Year: 2014

Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington's disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders. © 2014 Margulis and Finkbeiner.

Korb E.,Gladstone | Korb E.,University of California at San Francisco | Finkbeiner S.,Gladstone | Finkbeiner S.,University of California at San Francisco | Finkbeiner S.,Taube Koret Center for Huntingtons Disease Research
Trends in Neurosciences | Year: 2011

The activity-regulated cytoskeletal (Arc) gene encodes a protein that is critical for memory consolidation. Arc is one of the most tightly regulated molecules known: neuronal activity controls Arc mRNA induction, trafficking and accumulation, and Arc protein production, localization and stability. Arc regulates synaptic strength through multiple mechanisms and is involved in essentially every known form of synaptic plasticity. It also mediates memory formation and is implicated in multiple neurological diseases. In this review, we will discuss how Arc is regulated and used as a tool to study neuronal activity. We will also attempt to clarify how its molecular functions correspond to its requirement in various forms of plasticity, discuss Arc's role in behavior and disease, and highlight critical unresolved questions. © 2011 Elsevier Ltd.

Kwan W.,University of California at San Francisco | Kwan W.,Gladstone | Trager U.,Gladstone | Davalos D.,Gladstone | And 19 more authors.
Journal of Clinical Investigation | Year: 2012

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

Giorgini F.,University of Leicester | Huang S.-Y.,Gladstone | Huang S.-Y.,Taube Koret Center for Huntingtons Disease Research | Sathyasaikumar K.V.,University of Maryland Baltimore County | And 8 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Kynurenine 3-monooxygenase (KMO) is hypothesized to play a pivotal role in regulating tryptophan metabolism in health and disease. Results: Mice that were generated lacking KMO have alterations in the levels of several tryptophan metabolites. Conclusion: KMO is a critical regulator of tryptophan metabolism. Significance: KMO knock-out mice will be a useful research tool to dissect the biological and pathophysiological roles of tryptophan metabolism. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Nakamura K.,University of California at San Francisco | Nakamura K.,Gladstone | Nemani V.M.,University of California at San Francisco | Azarbal F.,University of California at San Francisco | And 18 more authors.
Journal of Biological Chemistry | Year: 2011

The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Sharma P.,Gladstone | Ando D.M.,Gladstone | Ando D.M.,University of California at San Francisco | Daub A.,Gladstone | And 7 more authors.
Methods in Enzymology | Year: 2012

Despite years of incremental progress in our understanding of diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), there are still no disease-modifying therapeutics. The discrepancy between the number of lead compounds and approved drugs may partially be a result of the methods used to generate the leads and highlights the need for new technology to obtain more detailed and physiologically relevant information on cellular processes in normal and diseased states. Our high-throughput screening (HTS) system in a primary neuron model can help address this unmet need. HTS allows scientists to assay thousands of conditions in a short period of time which can reveal completely new aspects of biology and identify potential therapeutics in the span of a few months when conventional methods could take years or fail all together. HTS in primary neurons combines the advantages of HTS with the biological relevance of intact, fully differentiated neurons which can capture the critical cellular events or homeostatic states that make neurons uniquely susceptible to disease-associated proteins. We detail methodologies of our primary neuron HTS assay workflow from sample preparation to data reporting. We also discuss the adaptation of our HTS system into high-content screening (HCS), a type of HTS that uses multichannel fluorescence images to capture biological events in situ, and is uniquely suited to study dynamical processes in living cells. © 2012 Elsevier Inc. All rights reserved.

Zwilling D.,University of California at San Francisco | Huang S.-Y.,University of California at San Francisco | Huang S.-Y.,Taube Koret Center for Huntingtons Disease Research | Sathyasaikumar K.V.,University of Maryland, Baltimore | And 23 more authors.
Cell | Year: 2011

Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases. © 2011 Elsevier Inc. All Rights Reserved.

Larkin P.B.,Gladstone | Larkin P.B.,University of California at San Francisco | Muchowski P.J.,Gladstone | Muchowski P.J.,University of California at San Francisco | Muchowski P.J.,Taube Koret Center for Huntingtons Disease Research
Journal of Huntington's Disease | Year: 2012

Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD. © 2012 - IOS Press and the authors. All rights reserved.

Tsvetkov A.S.,Gladstone | Tsvetkov A.S.,Taube Koret Center for Huntingtons Disease Research | Ando D.M.,University of California at San Francisco | Finkbeiner S.,University of California at San Francisco
Methods in Molecular Biology | Year: 2013

Misfolded proteins have been implicated in most of the major neurodegenerative diseases, and identifying drugs and pathways that protect neurons from the toxicity of misfolded proteins is of paramount importance. We invented a form of automated imaging and analysis called robotic microscopy that is well suited to the study of neurodegeneration. It enables the monitoring of large cohorts of individual neurons over their lifetimes as they undergo neurodegeneration. With automated analysis, multiple endpoints in neurons can be measured, including survival. Statistical approaches, typically reserved for engineering and clinical medicine, can be applied to these data in an unbiased fashion to discover whether factors contribute positively or negatively to neuronal fate and to quantify the importance of their contribution. Ultimately, multivariate dynamic models can be constructed from these data, which can provide a systems-level understanding of the neurodegenerative disease process and guide the rationale for the development of therapies. © Springer Science+Business Media New York 2013.

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