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Article: Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly.

Bennett, Craig L / Sopher, Bryce L / La Spada, Albert R

2020 Volume 6, Issue 6, Page(s) e04165

Abstract: The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and ... ...

Abstract	The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive
Language	English
Publishing date	2020-06-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2020.e04165
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Article: Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

Bennett, Craig L / Sopher, Bryce L / La Spada, Albert R

Heliyon. 2020 June, v. 6, no. 6

2020

Abstract: The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations ... ...

Abstract	The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.
Keywords	DNA replication ; amyotrophic lateral sclerosis ; cell culture ; cell cycle checkpoints ; cell nucleolus ; exosomes ; germplasm conservation ; homeostasis ; motor neurons ; transfection ; yeasts
Language	English
Dates of publication	2020-06
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2020.e04165
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Article ; Online: MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.

Branch, Mary Rose / Hsu, Cynthia L / Ohnishi, Kohta / Shen, Wen-Chuan / Lee, Elian / Meisenhelder, Jill / Winborn, Brett / Sopher, Bryce L / Taylor, J Paul / Hunter, Tony / La Spada, Albert R

Life science alliance

2023 Volume 6, Issue 8

Abstract: mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in ...

Abstract	mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.
MeSH term(s)	AMP-Activated Protein Kinases ; Sirtuin 1 ; Signal Transduction ; Amino Acids ; Mechanistic Target of Rapamycin Complex 1
Chemical Substances	AMP-Activated Protein Kinases (EC 2.7.11.31) ; Sirtuin 1 (EC 3.5.1.-) ; Amino Acids ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201525
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Article ; Online: Author Correction: Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

Nature medicine

2024 Volume 30, Issue 3, Page(s) 909–910

Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02778-7
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

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Article ; Online: Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.

Bennett, Craig L / Dastidar, Somasish / Arnold, Frederick J / McKinstry, Spencer U / Stockford, Cameron / Freibaum, Brian D / Sopher, Bryce L / Wu, Meilin / Seidner, Glen / Joiner, William / Taylor, J Paul / West, Ryan J H / La Spada, Albert R

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 164

Abstract: Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of ... ...

Abstract	Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)
MeSH term(s)	Humans ; Animals ; Amyotrophic Lateral Sclerosis/metabolism ; Dipeptides/genetics ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism ; Arginine/genetics ; Arginine/metabolism ; HEK293 Cells ; Motor Neurons/metabolism ; Drosophila/metabolism ; RNA/metabolism ; Frontotemporal Dementia/genetics ; DNA Repeat Expansion/genetics ; DNA Helicases/genetics ; RNA Helicases/genetics ; Multifunctional Enzymes/genetics
Chemical Substances	Dipeptides ; C9orf72 Protein ; Arginine (94ZLA3W45F) ; RNA (63231-63-0) ; SETX protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; RNA Helicases (EC 3.6.4.13) ; Multifunctional Enzymes ; C9orf72 protein, human
Language	English
Publishing date	2023-10-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01665-z
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Article ; Online: 4E-BP1 Protects Neurons from Misfolded Protein Stress and Parkinson's Disease Toxicity by Inducing the Mitochondrial Unfolded Protein Response.

Dastidar, Somasish Ghosh / Pham, Michael T / Mitchell, Matthew B / Yeom, Steven G / Jordan, Sarah / Chang, Angela / Sopher, Bryce L / La Spada, Albert R

The Journal of neuroscience : the official journal of the Society for Neuroscience

2020 Volume 40, Issue 45, Page(s) 8734–8745

Abstract: Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4E-BP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. ... ...

Abstract	Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4E-BP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. Overexpression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition on mTORC1 repression may be neuroprotective; however, whether 4E-BP1 overexpression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1-overexpressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1-overexpressing primary neurons. After documenting that 4E-BP1-overexpressing neurons are resistant to proteotoxic stress elicited by brefeldin A treatment, we exposed primary neurons to three different Parkinson's disease (PD)-linked toxins (rotenone, maneb, or paraquat) and documented significant protection in neurons from newborn male and female
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Animals ; Animals, Newborn ; Brefeldin A/pharmacology ; Cell Cycle Proteins/genetics ; Female ; Male ; Mice ; Mice, Transgenic ; Mitochondria/metabolism ; Neurons/pathology ; Parkinson Disease, Secondary/chemically induced ; Parkinson Disease, Secondary/genetics ; Primary Cell Culture ; Protein Biosynthesis/drug effects ; Protein Synthesis Inhibitors/pharmacology ; Protein Unfolding ; Proteostasis Deficiencies/genetics ; Proteostasis Deficiencies/pathology ; Rotenone/toxicity ; Uncoupling Agents/toxicity ; alpha-Synuclein/biosynthesis
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cell Cycle Proteins ; Eif4ebp1 protein, mouse ; Protein Synthesis Inhibitors ; Uncoupling Agents ; alpha-Synuclein ; Rotenone (03L9OT429T) ; Brefeldin A (20350-15-6)
Language	English
Publishing date	2020-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.0940-20.2020
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Zs.A 1668: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7.

Switonski, Pawel M / Delaney, Joe R / Bartelt, Luke C / Niu, Chenchen / Ramos-Zapatero, Maria / Spann, Nathanael J / Alaghatta, Akshay / Chen, Toby / Griffin, Emily N / Bapat, Jaidev / Sopher, Bryce L / La Spada, Albert R

Cell reports

2021 Volume 37, Issue 9, Page(s) 110062

Abstract: A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein ... ...

Abstract	A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.
MeSH term(s)	Acetylation ; Animals ; Ataxin-7/genetics ; Ataxin-7/metabolism ; Cerebellar Diseases/etiology ; Cerebellar Diseases/metabolism ; Cerebellar Diseases/pathology ; DNA Repair ; Female ; Histones/genetics ; Histones/metabolism ; Humans ; Male ; Mice ; Neurons/metabolism ; Neurons/pathology ; Peptides/genetics ; Spinocerebellar Ataxias/complications
Chemical Substances	Ataxin-7 ; Histones ; Peptides ; polyglutamine (26700-71-0)
Language	English
Publishing date	2021-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.110062
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Article ; Online: Neuronal susceptibility to beta-amyloid toxicity and ischemic injury involves histone deacetylase-2 regulation of endophilin-B1.

Wang, David B / Kinoshita, Chizuru / Kinoshita, Yoshito / Sopher, Bryce L / Uo, Takuma / Lee, Rona J / Kim, Joon Kyu / Murphy, Sean P / Dirk Keene, C / Garden, Gwenn A / Morrison, Richard S

Brain pathology (Zurich, Switzerland)

2018 Volume 29, Issue 2, Page(s) 164–175

Abstract: Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We ... ...

Abstract	Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/physiology ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Peptides/toxicity ; Animals ; Brain/metabolism ; Brain Ischemia/metabolism ; Disease Models, Animal ; GTP Phosphohydrolases/metabolism ; Gene Expression Regulation/genetics ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Histone Deacetylase 2/physiology ; Histone Deacetylases/genetics ; Histones/genetics ; Ischemia/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/physiology ; Stroke/physiopathology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Amyloid beta-Peptides ; Histones ; Sh3glb1 protein, mouse ; Hdac2 protein, mouse (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; GTP Phosphohydrolases (EC 3.6.1.-) ; Mfn2 protein, mouse (EC 3.6.1.-)
Language	English
Publishing date	2018-10-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.12647
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Zs.A 3585: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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Article ; Online: Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.

Ward, Jacqueline M / Stoyas, Colleen A / Switonski, Pawel M / Ichou, Farid / Fan, Weiwei / Collins, Brett / Wall, Christopher E / Adanyeguh, Isaac / Niu, Chenchen / Sopher, Bryce L / Kinoshita, Chizuru / Morrison, Richard S / Durr, Alexandra / Muotri, Alysson R / Evans, Ronald M / Mochel, Fanny / La Spada, Albert R

Cell reports

2019 Volume 26, Issue 5, Page(s) 1189–1202.e6

Abstract: Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance ... ...

Abstract	Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Ataxin-7/genetics ; Blood Glucose/metabolism ; Energy Metabolism ; Humans ; Kynurenine/metabolism ; Metabolomics ; Mice ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Diseases/blood ; Mitochondrial Diseases/metabolism ; Mitochondrial Diseases/pathology ; NAD/metabolism ; Neural Stem Cells/metabolism ; Organelles/metabolism ; Organelles/pathology ; Peptides/metabolism ; Phenotype ; Purkinje Cells/metabolism ; Reproducibility of Results ; Spinocerebellar Ataxias/blood ; Spinocerebellar Ataxias/metabolism ; Spinocerebellar Ataxias/pathology ; Trinucleotide Repeat Expansion/genetics ; Tryptophan/metabolism
Chemical Substances	Ataxin-7 ; Blood Glucose ; Peptides ; NAD (0U46U6E8UK) ; polyglutamine (26700-71-0) ; Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2019-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.01.028
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Article ; Online: Astroglial-targeted expression of the fragile X CGG repeat premutation in mice yields RAN translation, motor deficits and possible evidence for cell-to-cell propagation of FXTAS pathology.

Wenzel, H Jürgen / Murray, Karl D / Haify, Saif N / Hunsaker, Michael R / Schwartzer, Jared J / Kim, Kyoungmi / La Spada, Albert R / Sopher, Bryce L / Hagerman, Paul J / Raske, Christopher / Severijnen, Lies-Anne W F M / Willemsen, Rob / Hukema, Renate K / Berman, Robert F

Acta neuropathologica communications

2019 Volume 7, Issue 1, Page(s) 27

Abstract: The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late- ... ...

Abstract	The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence, were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of FMRpolyG, and deficits in motor function.
MeSH term(s)	Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Astrocytes/physiology ; Ataxia/genetics ; Ataxia/metabolism ; Ataxia/pathology ; Base Sequence ; Cell Communication/physiology ; Fragile X Mental Retardation Protein/biosynthesis ; Fragile X Mental Retardation Protein/genetics ; Fragile X Syndrome/genetics ; Fragile X Syndrome/metabolism ; Fragile X Syndrome/pathology ; Gene Expression ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Skills Disorders/genetics ; Motor Skills Disorders/metabolism ; Motor Skills Disorders/pathology ; Tremor/genetics ; Tremor/metabolism ; Tremor/pathology ; Trinucleotide Repeat Expansion/genetics
Chemical Substances	Fmr1 protein, mouse ; Fragile X Mental Retardation Protein (139135-51-6)
Language	English
Publishing date	2019-02-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-019-0677-7
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