Journal Article

DZNE-2026-00796

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.

Ziegler, M. ; Günter, C.DZNE* ; Alecu, J. E.Extern* ; Xue, X. ; Kim, H. M. ; Saffari, A. ; Davies, A. K. ; Sahin, M. ; Ebrahimi-Fakhari, D.

2026
JCI Insight Ann Arbor, Michigan

This record in other databases:    

Please use a persistent id in citations: doi:10.1172/jci.insight.202204

Abstract: Biallelic loss-of-function variants in adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at the trans-Golgi network, including autophagy-related protein 9A (ATG9A), leading to childhood-onset hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a neurodevelopmental and a 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 'druggable genome,' 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 ANPEP and NPM1 enhanced ATG9A availability outside the trans-Golgi network, suggesting that 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.

Keyword(s): Humans (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Vesicular Transport Proteins: metabolism (MeSH) ; Vesicular Transport Proteins: genetics (MeSH) ; CRISPR-Cas Systems (MeSH) ; Autophagy-Related Proteins: metabolism (MeSH) ; Autophagy-Related Proteins: genetics (MeSH) ; Neurons: metabolism (MeSH) ; Protein Transport: genetics (MeSH) ; Adaptor Protein Complex 4: genetics (MeSH) ; Adaptor Protein Complex 4: deficiency (MeSH) ; Adaptor Protein Complex 4: metabolism (MeSH) ; trans-Golgi Network: metabolism (MeSH) ; Spastic Paraplegia, Hereditary: genetics (MeSH) ; Spastic Paraplegia, Hereditary: metabolism (MeSH) ; Loss of Function Mutation (MeSH) ; Adaptor proteins ; Cell biology ; Genetic diseases ; Genetics ; Neurological disorders ; Neuroscience ; ATG9A protein, human ; Membrane Proteins ; Vesicular Transport Proteins ; Autophagy-Related Proteins ; Adaptor Protein Complex 4

---

Contributing Institute(s):

1. Axon Growth and Regeneration (AG Bradke)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

---

Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---