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AP-4-HSP is characterized by features of both a neurodevelopmental and degenerative neurological disease. To investigate the molecular mechanisms underlying AP-4-HSP and identify potential therapeutic targets, we conducted an arrayed CRISPR\/Cas9 loss-of-function screen of 8,478 genes, targeting the \u2018druggable genome\u2019, in a human neuronal model of AP-4 deficiency. Through this phenotypic screen and subsequent experiments, key modulators of ATG9A trafficking were identified, and complementary pathway analyses provided insights into the regulatory landscape of ATG9A transport. Knockdown of\n                  <jats:italic>ANPEP<\/jats:italic>\n                  and\n                  <jats:italic>NPM1<\/jats:italic>\n                  enhanced ATG9A availability outside the\n                  <jats:italic>trans<\/jats:italic>\n                  -Golgi network, suggesting they regulate ATG9A localization. These findings deepen our understanding of ATG9A trafficking in the context of AP-4 deficiency and offer a framework for the development of targeted interventions for AP-4-HSP.\n                <\/jats:p>","DOI":"10.1101\/2025.02.22.639634","type":"posted-content","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T19:15:18Z","timestamp":1740338118000},"source":"Crossref","is-referenced-by-count":0,"title":["Arrayed CRISPR\/Cas9 Loss-Of-Function Screen in a Neuronal Model of Adaptor Protein Complex 4 Deficiency Identifies Modulators of ATG9A Trafficking"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0504-7815","authenticated-orcid":false,"given":"Marvin","family":"Ziegler","sequence":"first","affiliation":[{"name":"Department of Neurology and F.M. 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