ArticleHuman molecular genetics2020
Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- A Risk Model Based on Ferroptosis-Related Genes OSMR, G0S2, IGFBP6, IGHG2, and FMOD Predicts Prognosis in Glioblastoma Multiforme.CNS neuroscience & therapeutics · 2025Pooled it
- CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.JCI insight · 2026Article
- Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia.Annals of clinical and translational neurology · 2026Article
- The AP-4 accessory protein tepsin exhibits multivalent binding to LC3B.Advances in biological regulation · 2026Article
- Splice effect of a synonymous variant inHuman mutation · 2026Article
- AP2M1 Is a Candidate Gene for Microcephaly and Intellectual Disability in 3q27.1 Deletions.American journal of medical genetics. Part A · 2025Article
- Hereditary Spastic Paraplegy Associated with the AP4S1 Gene: A Case Series Highlighting Diagnostic Pitfalls and Phenotypic Variability.Molecular syndromology · 2025Article
- Fetal and Perinatal Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.Annals of the Child Neurology Society · 2025Article
- The Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN): Clinical Trial Readiness for Hereditary Spastic Paraplegia.Neurology. Genetics · 2025Article
- Heterozygous variants in AP4S1 are not associated with a neurological phenotype.Annals of clinical and translational neurology · 2025Article
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- AP4B1 hypomorphic variants cause autosomal recessive adult-onset ataxia.Journal of neurology · 2025Article
- An update on autophagy disorders.Journal of inherited metabolic disease · 2025Review
- Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.EMBO molecular medicine · 2024Article
- Real-Time Analysis of Neuronal Cell Cultures for CNS Drug Discovery.Brain sciences · 2024Article
- AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.Nature medicine · 2024Article
- Tepsin binds LC3B to promote ATG9A trafficking and delivery.Molecular biology of the cell · 2024Article
- The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia.Progress in neurobiology · 2024Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia.Nature communications · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
29 authors at 13 institutions in 6 countries.
Funding
Abstract
Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3-5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.