@article {1623362,
	title = {Reduced nuclear NAD+ drives DNA damage and subsequent immune activation in the retina},
	journal = {Hum Mol Genet},
	volume = {31},
	number = {9},
	year = {2022},
	month = {2022 05 04},
	pages = {1370-1388},
	abstract = {Mutations in NMNAT1, a key enzyme involved in the synthesis of NAD+ in the nucleus, lead to an early onset severe inherited retinal degeneration (IRD). We aimed to understand the role of nuclear NAD+ in the retina and to identify the molecular mechanisms underlying NMNAT1-associated disease, using a mouse model that harbors the p.V9M mutation in Nmnat1 (Nmnat1V9M/V9M). We identified temporal transcriptional reprogramming in the retinas of Nmnat1V9M/V9M mice prior to retinal degeneration, which begins at 4\&nbsp;weeks of age, with no significant alterations in gene expression at 2\&nbsp;weeks of age and over 2600 differentially expressed genes by 3\&nbsp;weeks of age. Expression of the primary consumer of NAD+ in the nucleus, PARP1, an enzyme involved in DNA damage repair and transcriptional regulation, as well as 7 other PARP family enzymes, was elevated in the retinas of Nmnat1V9M/V9M. This was associated with elevated levels of DNA damage, PARP-mediated NAD+ consumption and migration of Iba1+/CD45+ microglia/macrophages to the subretinal space in the retinas of Nmnat1V9M/V9M mice. These findings suggest that photoreceptor cells are especially sensitive to perturbation of genome homeostasis, and that PARP-mediated cell death may play a role in other genetic forms of IRDs, and potentially other forms of neurodegeneration.},
	keywords = {DNA Damage, Humans, NAD, Nicotinamide-Nucleotide Adenylyltransferase, Poly(ADP-ribose) Polymerase Inhibitors, Retina, Retinal Degeneration},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddab324},
	author = {Brown, Emily E and Scandura, Michael J and Mehrotra, Sudeep and Wang, Yekai and Du, Jianhai and Pierce, Eric A}
}
