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  1. Article ; Online: Pathological phase transitions in ALS-FTD impair dynamic RNA-protein granules.

    Nedelsky, Natalia B / Taylor, J Paul

    RNA (New York, N.Y.)

    2021  Volume 28, Issue 1, Page(s) 97–113

    Abstract: The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of ... ...

    Abstract The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have epitomized this concept, as studies of ALS-FTD-causing mutations have yielded fundamental discoveries regarding the role of biomolecular condensation in organizing cellular contents while implicating disturbances in condensate dynamics as central drivers of neurodegeneration. Here we review this genetic evidence, highlight its intersection with patient pathology, and discuss how studies in model systems have revealed a role for aberrant condensation in neuronal dysfunction and death. We detail how multiple, distinct types of disease-causing mutations promote pathological phase transitions that disturb the dynamics and function of ribonucleoprotein (RNP) granules. Dysfunction of RNP granules causes pleiotropic defects in RNA metabolism and can drive the evolution of these structures to end-stage pathological inclusions characteristic of ALS-FTD. We propose that aberrant phase transitions of these complex condensates in cells provide a parsimonious explanation for the widespread cellular abnormalities observed in ALS as well as certain histopathological features that characterize late-stage disease.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Binding Sites ; Biomolecular Condensates/chemistry ; Biomolecular Condensates/metabolism ; Cell Death/genetics ; Cytoplasmic Ribonucleoprotein Granules/chemistry ; Cytoplasmic Ribonucleoprotein Granules/genetics ; Cytoplasmic Ribonucleoprotein Granules/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Frontotemporal Dementia/pathology ; Humans ; Molecular Dynamics Simulation ; Mutation ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Neurons/pathology ; Phase Transition ; Protein Binding ; RNA/chemistry ; RNA/genetics ; RNA/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/chemistry ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism
    Chemical Substances Nerve Tissue Proteins ; RNA-Binding Proteins ; Ribonucleoproteins ; RNA (63231-63-0)
    Language English
    Publishing date 2021-10-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1241540-6
    ISSN 1469-9001 ; 1355-8382
    ISSN (online) 1469-9001
    ISSN 1355-8382
    DOI 10.1261/rna.079001.121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease.

    Nedelsky, Natalia B / Taylor, J Paul

    Nature reviews. Neurology

    2019  Volume 15, Issue 5, Page(s) 272–286

    Abstract: Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein ( ... ...

    Abstract Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.
    MeSH term(s) Biophysics ; Brain/metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; Phase Transition ; Ribonucleoproteins/metabolism
    Chemical Substances Ribonucleoproteins
    Language English
    Publishing date 2019-03-13
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2491514-2
    ISSN 1759-4766 ; 1759-4758
    ISSN (online) 1759-4766
    ISSN 1759-4758
    DOI 10.1038/s41582-019-0157-5
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  3. Article ; Online: Inflammatory Bowel Disease at the Intersection of Autophagy and Immunity: Insights from Human Genetics

    Nedelsky, Natalia / Kuballa, Petric / Castoreno, Adam B. / Xavier, Ramnik J.

    Molecular Genetics of Inflammatory Bowel Disease

    Abstract: Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in ... ...

    Abstract Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in the process of autophagy, a lysosome-based degradation pathway. Although historically considered to be a relatively nonselective process of degradation of cytosolic contents, autophagy has recently been revealed to have several selective and immune-specific functions that are relevant to the maintenance of intestinal homeostasis, including xenophagy, mitophagy, antigen presentation, secretion, and inflammasome regulation. In this chapter, we review the evidence that links autophagy-related genes, their immune-specific functions, and possible mechanisms of IBD pathogenesis. We summarize the basic molecular events underlying general and selective autophagy, and present evidence suggesting possible pathogenic mechanisms revealed by studies of IBD-associated risk alleles of ATG16L1 and IRGM. Finally, we review chemical biology-based experimental approaches for identifying autophagy regulatory pathways that may have implications for the development of therapeutics.
    Keywords covid19
    Publisher PMC
    Document type Article ; Online
    DOI 10.1007/978-3-030-28703-0_14
    Database COVID19

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  4. Article: Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection.

    Nedelsky, Natalia B / Todd, Peter K / Taylor, J Paul

    Biochimica et biophysica acta

    2008  Volume 1782, Issue 12, Page(s) 691–699

    Abstract: Protein degradation is an essential cellular function that, when dysregulated or impaired, can lead to a wide variety of disease states. The two major intracellular protein degradation systems are the ubiquitin-proteasome system (UPS) and autophagy, a ... ...

    Abstract Protein degradation is an essential cellular function that, when dysregulated or impaired, can lead to a wide variety of disease states. The two major intracellular protein degradation systems are the ubiquitin-proteasome system (UPS) and autophagy, a catabolic process that involves delivery of cellular components to the lysosome for degradation. While the UPS has garnered much attention as it relates to neurodegenerative disease, important links between autophagy and neurodegeneration have also become evident. Furthermore, recent studies have revealed interaction between the UPS and autophagy, suggesting a coordinated and complementary relationship between these degradation systems that becomes critical in times of cellular stress. Here we describe autophagy and review evidence implicating this system as an important player in the pathogenesis of neurodegenerative disease. We discuss the role of autophagy in neurodegeneration and review its neuroprotective functions as revealed by experimental manipulation in disease models. Finally, we explore potential parallels and connections between autophagy and the UPS, highlighting their collaborative roles in protecting against neurodegenerative disease.
    MeSH term(s) Animals ; Autophagy/physiology ; Humans ; Neurodegenerative Diseases/physiopathology ; Neurodegenerative Diseases/therapy ; Neuroprotective Agents/therapeutic use ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism
    Chemical Substances Neuroprotective Agents ; Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2008-12
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2008.10.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Inflammatory Bowel Disease at the Intersection of Autophagy and Immunity: Insights from Human Genetics

    Nedelsky, Natalia B. / Kuballa, Petric / Castoreno, Adam B. / Xavier, Ramnik J.

    Molecular Genetics of Inflammatory Bowel Disease

    Abstract: Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in ... ...

    Abstract Studies using human genetics have identified more than 160 loci that affect the risk of developing inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Several of these genes have been found to play key roles in the process of autophagy, a lysosome-based degradation pathway. Although historically considered to be a relatively nonselective process of degradation of cytosolic contents, autophagy has recently been revealed to have several selective and immune-specific functions that are relevant to the maintenance of intestinal homeostasis, including xenophagy, mitophagy, antigen presentation, secretion, and inflammasome regulation. In this chapter, we review the evidence that links autophagy-related genes, their immune-specific functions, and possible mechanisms of IBD pathogenesis. We summarize the basic molecular events underlying general and selective autophagy and present evidence suggesting possible pathogenic mechanisms revealed by studies of IBD-associated risk alleles of ATG16L1 and IRGM. Finally, we review chemical biology-based experimental approaches for identifying autophagy regulatory pathways that may have implications for the development of therapeutics.
    Keywords covid19
    Publisher PMC
    Document type Article ; Online
    DOI 10.1007/978-1-4614-8256-7_12
    Database COVID19

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  6. Article ; Online: Orthobunyavirus entry into neurons and other mammalian cells occurs via clathrin-mediated endocytosis and requires trafficking into early endosomes.

    Hollidge, Bradley S / Nedelsky, Natalia B / Salzano, Mary-Virginia / Fraser, Jonathan W / González-Scarano, Francisco / Soldan, Samantha S

    Journal of virology

    2012  Volume 86, Issue 15, Page(s) 7988–8001

    Abstract: La Crosse virus (LACV) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern United States, where it is considered an emerging human pathogen. No specific therapies or vaccines are available for LACV or any ... ...

    Abstract La Crosse virus (LACV) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern United States, where it is considered an emerging human pathogen. No specific therapies or vaccines are available for LACV or any other orthobunyaviruses. Inhibition of LACV entry into cells is a potential target for therapeutic intervention, but this approach is limited by our current knowledge of the entry process. Here, we determined that clathrin-mediated endocytosis is the primary mechanism of orthobunyavirus entry and identified key cellular factors in this process. First, we demonstrated that LACV colocalized with clathrin shortly after infection in HeLa cells; we then confirmed the functional requirement of dynamin- and clathrin-mediated endocytosis for orthobunyavirus entry using several independent assays and, importantly, extended these findings to primary neuronal cultures. We also determined that macropinocytosis and caveolar endocytosis, both established routes of virus entry, are not critical for cellular entry of LACV. Moreover, we demonstrated that LACV infection is dependent on Rab5, which plays an important regulatory role in early endosomes, but not on Rab7, which is associated with late endosomes. These findings provide the first description of bunyavirus entry into cells of the central nervous system, where infection can cause severe neurological disease, and will aid in the design and development of antivirals and therapeutics that may be useful in the treatment of LACV and, more broadly, arboviral infections of the central nervous system.
    MeSH term(s) Animals ; Chlorocebus aethiops ; Clathrin/genetics ; Clathrin/metabolism ; Cricetinae ; Encephalitis, California/drug therapy ; Encephalitis, California/genetics ; Encephalitis, California/metabolism ; Endocytosis ; Endosomes/genetics ; Endosomes/metabolism ; Endosomes/virology ; HeLa Cells ; Humans ; La Crosse virus/genetics ; La Crosse virus/metabolism ; Vero Cells ; Virus Internalization ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; rab5 GTP-Binding Proteins/genetics ; rab5 GTP-Binding Proteins/metabolism
    Chemical Substances Clathrin ; rab7 protein (152989-05-4) ; rab GTP-Binding Proteins (EC 3.6.5.2) ; rab5 GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2012-05-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00140-12
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    Zs.A 609: Show issues Location:
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  7. Article ; Online: Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy.

    Nedelsky, Natalia B / Pennuto, Maria / Smith, Rebecca B / Palazzolo, Isabella / Moore, Jennifer / Nie, Zhiping / Neale, Geoffrey / Taylor, J Paul

    Neuron

    2010  Volume 67, Issue 6, Page(s) 936–952

    Abstract: Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of ... ...

    Abstract Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary, but not sufficient, for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases.
    MeSH term(s) Actins/metabolism ; Animals ; Animals, Genetically Modified ; Blindness/genetics ; Blindness/pathology ; Cell Line, Transformed ; Disease Models, Animal ; Drosophila ; Drosophila Proteins/genetics ; Eye/metabolism ; Eye/pathology ; Female ; Furylfuramide/metabolism ; Gene Expression Profiling/methods ; Gene Expression Regulation/genetics ; Humans ; Larva/physiology ; Locomotion/genetics ; Motor Neurons/metabolism ; Muscular Disorders, Atrophic/etiology ; Muscular Disorders, Atrophic/genetics ; Muscular Disorders, Atrophic/pathology ; Mutagenesis/physiology ; Mutation/genetics ; Neuromuscular Junction/pathology ; Oligonucleotide Array Sequence Analysis/methods ; Phenotype ; Principal Component Analysis ; Protein Transport/genetics ; RNA Interference/physiology ; Receptors, Androgen/chemistry ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Salivary Glands/metabolism ; Salivary Glands/pathology ; Statistics, Nonparametric ; Transfection/methods ; Trinucleotide Repeat Expansion ; Tubulin/metabolism
    Chemical Substances Actins ; Drosophila Proteins ; Receptors, Androgen ; Tubulin ; Furylfuramide (054NR2135Y)
    Language English
    Publishing date 2010-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2010.08.034
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    Zs.A 2496: Show issues Location:
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    Zs.MG 92: Show issues

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  8. Article ; Online: B2 attenuates polyglutamine-expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy.

    Palazzolo, Isabella / Nedelsky, Natalia B / Askew, Caitlin E / Harmison, George G / Kasantsev, Aleksey G / Taylor, J Paul / Fischbeck, Kenneth H / Pennuto, Maria

    Journal of neuroscience research

    2010  Volume 88, Issue 10, Page(s) 2207–2216

    Abstract: Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a ... ...

    Abstract Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brainstem and spinal cord. We found that B2 increases the deposition of mutant AR into nuclear inclusions, without altering the ligand-induced aggregation, expression, or subcellular distribution of the mutant protein. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. We show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Bulbo-Spinal Atrophy, X-Linked/drug therapy ; Bulbo-Spinal Atrophy, X-Linked/metabolism ; Cell Line ; Disease Models, Animal ; Drosophila melanogaster ; Humans ; Intracellular Space/drug effects ; Intracellular Space/metabolism ; Intranuclear Inclusion Bodies/drug effects ; Intranuclear Inclusion Bodies/metabolism ; Ligands ; Mutation ; Neuroprotective Agents/pharmacology ; Nitroquinolines/pharmacology ; Peptides/metabolism ; Piperazines/pharmacology ; Protein Multimerization ; Rats ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism
    Chemical Substances 5-(4-(4-chlorobenzoyl)-1-piperazinyl)-8-nitroquinoline ; Ligands ; Neuroprotective Agents ; Nitroquinolines ; Peptides ; Piperazines ; Receptors, Androgen ; polyglutamine (26700-71-0)
    Language English
    Publishing date 2010-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 195324-2
    ISSN 1097-4547 ; 0360-4012
    ISSN (online) 1097-4547
    ISSN 0360-4012
    DOI 10.1002/jnr.22389
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  9. Article ; Online: Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.

    Cao, Zhifang / Conway, Kara L / Heath, Robert J / Rush, Jason S / Leshchiner, Elizaveta S / Ramirez-Ortiz, Zaida G / Nedelsky, Natalia B / Huang, Hailiang / Ng, Aylwin / Gardet, Agnès / Cheng, Shih-Chin / Shamji, Alykhan F / Rioux, John D / Wijmenga, Cisca / Netea, Mihai G / Means, Terry K / Daly, Mark J / Xavier, Ramnik J

    Immunity

    2015  Volume 43, Issue 4, Page(s) 715–726

    Abstract: CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory ... ...

    Abstract CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.
    MeSH term(s) Adjuvants, Immunologic/pharmacology ; Animals ; CARD Signaling Adaptor Proteins/chemistry ; CARD Signaling Adaptor Proteins/deficiency ; CARD Signaling Adaptor Proteins/genetics ; CARD Signaling Adaptor Proteins/physiology ; Candidiasis, Invasive/genetics ; Candidiasis, Invasive/immunology ; Colitis/chemically induced ; Colitis/genetics ; Colitis/prevention & control ; Cytokines/biosynthesis ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Genes, Dominant ; Genetic Predisposition to Disease ; HEK293 Cells ; HeLa Cells ; Humans ; Inflammatory Bowel Diseases/genetics ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Protein Interaction Mapping ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/physiology ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Receptors, Angiotensin/chemistry ; Receptors, Angiotensin/deficiency ; Receptors, Angiotensin/physiology ; Receptors, Endothelin/chemistry ; Receptors, Endothelin/deficiency ; Receptors, Endothelin/physiology ; Recombinant Fusion Proteins/metabolism ; Signal Transduction ; Specific Pathogen-Free Organisms ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/physiology ; Ubiquitination
    Chemical Substances Adjuvants, Immunologic ; CARD Signaling Adaptor Proteins ; CARD9 protein, human ; Card9 protein, mouse ; Cytokines ; Dear1 protein, mouse ; Protein Isoforms ; Receptors, Angiotensin ; Receptors, Endothelin ; Recombinant Fusion Proteins ; Tripartite Motif Proteins ; TRIM62 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2015-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2015.10.005
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    Zs.MG 69: Show issues

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  10. Article ; Online: HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS.

    Pandey, Udai Bhan / Nie, Zhiping / Batlevi, Yakup / McCray, Brett A / Ritson, Gillian P / Nedelsky, Natalia B / Schwartz, Stephanie L / DiProspero, Nicholas A / Knight, Melanie A / Schuldiner, Oren / Padmanabhan, Ranjani / Hild, Marc / Berry, Deborah L / Garza, Dan / Hubbert, Charlotte C / Yao, Tso-Pang / Baehrecke, Eric H / Taylor, J Paul

    Nature

    2007  Volume 447, Issue 7146, Page(s) 859–863

    Abstract: A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular ... ...

    Abstract A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.
    MeSH term(s) Animals ; Autophagy/genetics ; Autophagy/physiology ; Disease Models, Animal ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Histone Deacetylase 6 ; Histone Deacetylases/metabolism ; Humans ; Muscular Disorders, Atrophic/genetics ; Muscular Disorders, Atrophic/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Peptides/genetics ; Peptides/metabolism ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism ; Ubiquitin/metabolism
    Chemical Substances Drosophila Proteins ; Peptides ; Receptors, Androgen ; Ubiquitin ; polyglutamine (26700-71-0) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; HDAC6 protein, Drosophila (EC 3.5.1.98) ; Histone Deacetylase 6 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2007-06-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature05853
    Database MEDical Literature Analysis and Retrieval System OnLINE

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