Abstract
The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. Furthermore we show that the iPLA2-VIA knockout fly model provides a useful platform for the further study of PLA2G6-associated neurodegeneration.
Highlights
The PLA2G6 gene encodes an 85-kDa group VI calciumindependent phospholipase A2 beta (PLA2G6)
Given that loss of iPLA2-VIA led to increased lipid peroxidation and mitochondrial dysfunction in Drosophila, we examined fibroblasts taken from a patient with a known homozygous p.R747W mutation in PLA2G6 causing dystonia-parkinsonism (Paisan-Ruiz et al, 2009)
These findings lead to the question as to how loss of normal PLA2G6 gene function leads to abnormal mitochondrial morphology, and whether mitochondrial dysfunction is an early feature of PLA2G6-associated neurodegeneration
Summary
The PLA2G6 gene encodes an 85-kDa group VI calciumindependent phospholipase A2 beta (PLA2G6). Humans with PLA2G6 mutations can show progressive cognitive and motor skill regression, as displayed in disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome (Khateeb et al, 2006; Morgan et al, 2006). Infantile neuroaxonal dystrophy is a neurodegenerative disease with onset in infancy and fatality in the teenage years or in early adulthood. It is characterized neuropathologically by axonal swelling and the presence of spheroid bodies in the central and peripheral nervous systems in addition to hallmark cerebellar atrophy. Post-mortem examination of the brain of a patient with neurodegeneration with brain iron accumulation associated with homozygous PLA2G6 mutations demonstrated both Parkinson’s and Alzheimer’s disease pathology with widespread Lewy bodies, dystrophic neurites and cortical neuronal neurofibrillary tangles (Gregory et al, 2008)
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