Disrupted Membrane Homeostasis and Accumulation of Ubiquitinated Proteins in a Mouse Model of Infantile Neuroaxonal Dystrophy Caused by PLA2G6 Mutations
| Autor: | Ibrahim Malik, Mary Wohltmann, John Turk, Paul T. Kotzbauer, David F. Wozniak, Laura Montier, Richard W. Gross, Robert E. Schmidt, David J. Mancuso |
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| Rok vydání: | 2008 |
| Předmět: |
Pathology
medicine.medical_specialty Neurodegeneration with brain iron accumulation Lameness Animal Neuroaxonal Dystrophies Protein degradation medicine.disease_cause Inclusion bodies Pathology and Forensic Medicine Group VI Phospholipases A2 Infantile neuroaxonal dystrophy Pathogenesis Mice Microscopy Electron Transmission Ubiquitin medicine Neuropil Animals Homeostasis Gait Disorders Neurologic Inclusion Bodies Mice Knockout Mutation Membranes biology Ubiquitination Brain medicine.disease Immunohistochemistry Axons Cell biology Disease Models Animal medicine.anatomical_structure biology.protein Regular Articles |
| Zdroj: | The American Journal of Pathology. 172:406-416 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2008.070823 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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