Mark Zylka, Ph.D.
University of North Carolina at Chapel Hill
DP1ES024088, R56ES028236, R35ES028366
Loss of the enzyme topoisomerase 1 (TOP1) leads to DNA damage in neurons and neurodegeneration, according to a new NIEHS-funded study. TOP1 plays an important role in facilitating the expression of long genes that are important for neuronal function. According to the research team, these data indicate that TOP1 maintains proper gene function in the central nervous system.
To evaluate the role of TOP1 in neurodegeneration, the researchers deleted TOP1 in mouse neurons and examined behavior, development, and underlying indicators of neurodegeneration, such as inflammation. Although the neurons developed normally, mice lacking TOP1 showed motor deficits and died prematurely. Those mice also showed signs of early neurodegeneration, with brains 3.5-times smaller at postnatal day 15 compared with controls. The researchers identified extensive inflammation in the brains of mice lacking TOP1, along with DNA damage and decreased expression of 132 long genes that are critical for normal neurodevelopment and function.
The team reported that mice lacking TOP1 had lower levels of nicotinamide adenine dinucleotide (NAD-plus), a compound critical in energy metabolism. When mice without TOP1 received supplemental NAD-plus, they lived 30% longer, had less inflammation, and showed improved neuronal survival. Neurodegeneration was partially improved, yet the mice still had motor deficits. This result indicated that when TOP1 was compromised, reducing neuronal loss was not sufficient to limit behavioral decline.
Citation: Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, Simon JM, Yuan H, Li Z, McConnell MJ, Zylka MJ. 2020. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun 11(1):1962.