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Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020), Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Portfolio, 2020.
-
Abstract
- 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+) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.<br />Topoisomerase 1 (TOP1) relieves DNA torsional stress during transcription and facilitates the expression of long neuronal genes. Here we show that deletion of Top1 in excitatory neurons leads to early onset neurodegeneration that is partially dependent on p53/PARP1 activation and NAD+ depletion.
- Subjects :
- 0301 basic medicine
Genome instability
Cell death in the nervous system
Poly (ADP-Ribose) Polymerase-1
General Physics and Astronomy
Apoptosis
Pyridinium Compounds
Nicotinamide adenine dinucleotide
Hippocampus
chemistry.chemical_compound
Mice
0302 clinical medicine
PARP1
lcsh:Science
Cerebral Cortex
Mice, Knockout
Neurons
Multidisciplinary
Neurodegeneration
Neurodegenerative Diseases
Cell biology
DNA Topoisomerases, Type I
Transcription
Niacinamide
DNA damage
Science
Biology
Motor Activity
General Biochemistry, Genetics and Molecular Biology
Article
Genomic Instability
03 medical and health sciences
medicine
Animals
Neuroinflammation
Inflammation
Mortality, Premature
General Chemistry
medicine.disease
NAD
030104 developmental biology
chemistry
Nicotinamide riboside
Mutation
lcsh:Q
NAD+ kinase
030217 neurology & neurosurgery
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....fd9917856ceea64db8f49013740259b5