title: Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations.
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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Malik
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: David J
authors.initials: DJ
authors.lastname: Mancuso
authors.forename: Laura
authors.initials: L
authors.lastname: Montier
authors.forename: Mary
authors.initials: M
authors.lastname: Wohltmann
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.forename: Paul T
authors.initials: PT
authors.lastname: Kotzbauer
mesh_terms: D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D020233:Gait Disorders, Neurologic / Q000209:etiology; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D006706:Homeostasis; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000648:ultrastructure*; D007794:Lameness, Animal / Q000209:etiology; D008566:Membranes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D054875:Ubiquitination
chemical_list: D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human