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

Giulia Fragola, Angela M. Mabb, Bonnie Taylor-Blake, Jesse K. Niehaus, William D. Chronister, Hanqian Mao, Jeremy M. Simon, Hong Yuan, Zibo Li, Michael J. McConnell and Mark J. Zylka ()
Additional contact information
Giulia Fragola: University of North Carolina at Chapel Hill
Angela M. Mabb: Georgia State University
Bonnie Taylor-Blake: University of North Carolina at Chapel Hill
Jesse K. Niehaus: University of North Carolina at Chapel Hill
William D. Chronister: University of Virginia School of Medicine
Hanqian Mao: University of North Carolina at Chapel Hill
Jeremy M. Simon: University of North Carolina at Chapel Hill
Hong Yuan: University of North Carolina at Chapel Hill
Zibo Li: University of North Carolina at Chapel Hill
Michael J. McConnell: University of Virginia School of Medicine
Mark J. Zylka: University of North Carolina at Chapel Hill

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-15794-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15794-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-15794-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().