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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\u00a0weeks of age, with no significant alterations in gene expression at 2\u00a0weeks of age and over 2600 differentially expressed genes by 3\u00a0weeks 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddab324","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T12:21:33Z","timestamp":1636114893000},"page":"1370-1388","source":"Crossref","is-referenced-by-count":13,"title":["Reduced nuclear NAD+ drives DNA damage and subsequent immune activation in the retina"],"prefix":"10.1093","volume":"31","author":[{"given":"Emily E","family":"Brown","sequence":"first","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J","family":"Scandura","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudeep","family":"Mehrotra","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yekai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, WV, 26506, USA"},{"name":"Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhai","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, WV, 26506, USA"},{"name":"Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric A","family":"Pierce","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"2022051716214446600_ref1","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1038\/ng.2361","article-title":"NMNAT1 mutations cause Leber congenital amaurosis","volume":"44","author":"Falk","year":"2012","journal-title":"Nat. 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