ArticleThe American journal of pathology2008
Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations.
Article in The American journal of pathology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 159 citations in OpenAlex.
- Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges.Neurology international · 2026Review
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- Integrated Proteomics and Metabolomics Analysis Reveals Potential Pathways Underlying Onion-Mediated Regulation of Spleen Immune Function in Liangshan Black Sheep.Veterinary sciences · 2026Article
- Neurodevelopmental regression Due to PLA2G6-associated neurodegeneration despite normal brain MRI: a case report.Frontiers in pediatrics · 2026Article
- Peptide Activator Stabilizes DJ-1 Structure and Enhances Its Activity.International journal of molecular sciences · 2024Article
- iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.Journal of neuroinflammation · 2024Article
- Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?Cells · 2024Review
- Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.National science review · 2024Article
- Iron chelators: as therapeutic agents in diseases.Annals of medicine and surgery (2012) · 2024Review
- The PNPLA family of enzymes: characterisation and biological role.Arhiv za higijenu rada i toksikologiju · 2023Article
- Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration.Neural regeneration research · 2023Review
- Molecular basis of unique specificity and regulation of group VIA calcium-independent phospholipase APharmacology & therapeutics · 2023Review
- Article
- Neurodegenerative Disorders: Spotlight on Sphingolipids.International journal of molecular sciences · 2021Review
- Parkinson's Disease-Related Genes and Lipid Alteration.International journal of molecular sciences · 2021Review
- Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy.Molecular genetics and genomics : MGG · 2021Article
- iPLA2-VIA is required for healthy aging of neurons, muscle, and the female germline in Drosophila melanogaster.PloS one · 2021Article
- Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).Antioxidants (Basel, Switzerland) · 2020Review
- Metabolic Effects of Selective Deletion of Group VIA Phospholipase ABiomolecules · 2020Article
- Overdosing on iron: Elevated iron and degenerative brain disorders.Experimental biology and medicine (Maywood, N.J.) · 2020Review
30 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 2 countries.
Funding
Abstract
Mutations in the PLA2G6 gene, which encodes group VIA calcium-independent phospholipase A2 (iPLA(2)beta), were recently identified in patients with infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation. A pathological hallmark of these childhood neurodegenerative diseases is the presence of distinctive spheroids in distal axons that contain accumulated membranes. We used iPLA(2)beta-KO mice generated by homologous recombination to investigate neurodegenerative consequences of PLA2G6 mutations. iPLA(2)beta-KO mice developed age-dependent neurological impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. The primary abnormality underlying this neurological impairment was the formation of spheroids containing tubulovesicular membranes remarkably similar to human INAD. Spheroids were strongly labeled with anti-ubiquitin antibodies. Accumulation of ubiquitinated protein in spheroids was evident in some brain regions as early as 4 months of age, and the onset of motor impairment correlated with a dramatic increase in ubiquitin-positive spheroids throughout the neuropil in nearly all brain regions. Furthermore accumulating ubiquitinated proteins were observed primarily in insoluble fractions of brain tissue, implicating protein aggregation in this pathogenic process. These results indicate that loss of iPLA(2)beta causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. iPLA(2)beta-KO mice will be useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration with brain iron accumulation.
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