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Washington University Experience | NEURODEGENERATION | Infantile Neuroaxonal Dystrophy (INAD) | 3A0 Case 3 History
Case 3 An animal model of PLAN. ---- Kotzbauer et al., (2008) used iPLA2-KO mice generated by homologous recombination to investigate neurodegenerative consequences of PLA2G6 mutations, which encode group VIA calcium-independent phospholipase A2 (iPLA2), and have been identified in patients with 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. iPLA2-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 in these animals 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. 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 iPLA2 causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. (Kotzbauer et al., Am J Pathol 2008, 172:406 –416)
