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Axon loss is a common and early driver of disability across neurodegenerative diseases, peripheral neuropathies, traumatic injury, and neurotoxic chemotherapy. A major conceptual advance from the Wallerian degeneration research field is that axons can execute an intrinsic self-destruction program (programmed axon degeneration) that is actively suppressed in healthy axons. NMNAT2 acts as the central endogenous axon maintenance factor in this system: it is highly labile; it must be continuously delivered from the soma into axons; and when its levels fall, axon degeneration is triggered through activation of SARM1, an NAD-consuming enzyme. This makes NMNAT2 a mechanistically grounded therapeutic node: stabilizing it, improving axonal delivery, or blocking downstream SARM1 can strongly preserve axons in diverse injury and disease contexts. NMNAT2 is a short-lived axonal NAD biosynthetic enzyme that maintains a low NMN:NAD ratio to restrain the executioner SARM1, thereby preserving axon integrity. This review integrates NMNAT2\u2019s localization-dependent pools, turnover mechanisms, upstream stressors, downstream SARM1 signaling, and engineered and disease-associated variants. A localization-aware representation of NMNAT2\u2019s functions, trafficking, proteostatic regulation, upstream stressors, and genetic variants should enable targeted experimental design and therapeutic hypothesis generation aimed at stabilizing axons. Here the functional landscape and localization of NMNAT2 in neurodegeneration is examined, ending with gaps identified in the literature and strategies to address these.<\/jats:p>","DOI":"10.1177\/10738584261476959","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:37:24Z","timestamp":1787647044000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["NMNAT2 Functional Landscape and Localization in Programmed Axon Degeneration"],"prefix":"10.1177","author":[{"given":"Alan","family":"Nicol","sequence":"first","affiliation":[{"name":"Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia"},{"name":"Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-9951","authenticated-orcid":false,"given":"Flora","family":"Hui","sequence":"additional","affiliation":[{"name":"Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Brancale","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, University of Chemistry and Technology in Prague, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6194-8397","authenticated-orcid":false,"given":"Pete A.","family":"Williams","sequence":"additional","affiliation":[{"name":"Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia"},{"name":"Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia"},{"name":"Division of Eye and Vision, Department of Clinical Neuroscience, St Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105808"},{"key":"e_1_3_2_3_1","doi-asserted-by":"crossref","unstructured":"Ali YO et al. 2016. NMNAT2:HSP90 complex mediates proteostasis in proteinopathies. PLoS Biol. 14(6):e1002472.","DOI":"10.1371\/journal.pbio.1002472"},{"key":"e_1_3_2_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep46780"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.103812"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04480-2"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508660200"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.08.017"},{"key":"e_1_3_2_9_1","doi-asserted-by":"crossref","unstructured":"Carlton L et al. 2026. 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