Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration.

Animals Apoptosis / drug effects Cerebral Cortex / enzymology DNA Damage DNA Topoisomerases, Type I / deficiency Genomic Instability Hippocampus / enzymology Inflammation Mice Mice, Knockout Mortality, Premature Motor Activity Mutation NAD / administration & dosage Neurodegenerative Diseases / drug therapy Neurons / drug effects Niacinamide / administration & dosage Poly (ADP-Ribose) Polymerase-1 / metabolism Pyridinium Compounds

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
23 04 2020
Historique:
received: 01 07 2019
accepted: 28 03 2020
entrez: 25 4 2020
pubmed: 25 4 2020
medline: 1 8 2020
Statut: epublish

Résumé

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD

Identifiants

DOI: 10.1038/s41467-020-15794-9 PMID: 32327659 PMC: PMC7181881
pubmed: 32327659
doi: 10.1038/s41467-020-15794-9
pii: 10.1038/s41467-020-15794-9
pmc: PMC7181881
doi:

Substances chimiques

Pyridinium Compounds 0
nicotinamide-beta-riboside 0I8H2M0L7N
NAD 0U46U6E8UK
Niacinamide 25X51I8RD4
Parp1 protein, mouse EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1 EC 2.4.2.30
DNA Topoisomerases, Type I EC 5.99.1.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1962

Subventions

Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES028366
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS045892
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD079124
Pays : United States
Organisme : NIEHS NIH HHS
ID : DP1 ES024088
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG058663
Pays : United States
Organisme : NIEHS NIH HHS
ID : R56 ES028236
Pays : United States

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Auteurs

Giulia Fragola (G)

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
ORCID: 0000-0001-9114-9836

Angela M Mabb (AM)

Neuroscience Institute, Georgia State University, Atlanta, GA, 30303, USA.
ORCID: 0000-0002-3000-8690

Bonnie Taylor-Blake (B)

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Jesse K Niehaus (JK)

UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
ORCID: 0000-0002-6800-4134

William D Chronister (WD)

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

Hanqian Mao (H)

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Jeremy M Simon (JM)

UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
ORCID: 0000-0003-3906-1663

Hong Yuan (H)

Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Biomedical Imaging Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Zibo Li (Z)

Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Biomedical Imaging Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
ORCID: 0000-0002-1063-0298

Michael J McConnell (MJ)

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Center for Public Health Genomics, University of Virginia, School of Medicine, Charlottesville, VA, 22908, USA.

Mark J Zylka (MJ)

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. zylka@med.unc.edu.
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. zylka@med.unc.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › ADN topoisomérases de type I › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Phénomènes génétiques › Instabilité du génome › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Hippocampe › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Registre civil › Mortalité › Mortalité prématurée › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système locomoteur › Mouvement › Activité motrice › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › NAD › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Cellules › Neurones › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Acides nicotiniques › Nicotinamide › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Glycosyltransferase › Pentosyltransferases › ADP ribose transferases › Poly(ADP-ribose) polymerases › Poly (ADP-Ribose) polymerase-1 › Deletion of Topoisomerase 1 in excitatory...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Composés de pyridinium › Deletion of Topoisomerase 1 in excitatory...