ArticlePLoS genetics2018
Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 120 citations in OpenAlex.
- Compartment-Specific Lysosomal Heterogeneity in Microglia Is Regulated by Adaptor Protein Complex-4.bioRxiv : the preprint server for biology · 2026Article
- Allele frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility.American journal of human genetics · 2026Article
- 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
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- The AP-4 accessory protein tepsin exhibits multivalent binding to LC3B.Advances in biological regulation · 2026Article
- Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.Translational neurodegeneration · 2025Article
- Article
- S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.Autophagy · 2025Article
- Fetal and Perinatal Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.Annals of the Child Neurology Society · 2025Article
- Progress on multifunctional transmembrane protein ATG9A.Cell communication and signaling : CCS · 2025Review
- Identification of comorbid genes between type 2 diabetes and migraine through peripheral blood single-cell and Mendelian randomization analysis.The journal of headache and pain · 2025Article
- Unveiling mysteries of aging: the potential of melatonin in preventing neurodegenerative diseases in older adults.Biogerontology · 2025Review
- Article
- Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.Molecular neurobiology · 2025Review
- Turning garbage into gold: Autophagy in synaptic function.Current opinion in neurobiology · 2025Review
- Review
- Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.EMBO molecular medicine · 2024Article
- AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.Nature medicine · 2024Article
- Biallelic BORCS8 variants cause an infantile-onset neurodegenerative disorder with altered lysosome dynamics.Brain : a journal of neurology · 2024Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
Abstract
The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons. These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder.
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