1. Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
- Author
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Mark J. Zylka, Angela M. Mabb, Bonnie Taylor-Blake, William D. Chronister, Jeremy M. Simon, Hong Yuan, Zibo Li, Michael J. McConnell, Giulia Fragola, Jesse K. Niehaus, and Hanqian Mao
- 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 - 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., 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.
- Published
- 2020