Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
Open Access
- 23 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-13
- https://doi.org/10.1038/s41467-020-15794-9
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.Funding Information
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124, U54HD079124, U54HD079124)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (P30NS045892, P30NS045892)
- U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (R56ES028236, R35ES028366)
- U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R56AG058663)
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development
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