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FB2026_02
,
released June 18, 2026
A number of neurodegenerative diseases are associated with defects in the human gene PLA2G6 (phospholipase A2, group VI). See links in 'Related Diseases' for information on specific diseases. Loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities. There is a single fly ortholog, iPLA2-VIA, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and amorphic mutations caused by imprecise excision of TE insertions have been generated.
UAS constructs of the human Hsap\PLA2G6 have been introduced into flies, including wild-type and mutant forms. Functional complementation (heterologous rescue) is observed for the bang-sensitive phenotype of amorphic alleles of Dmel\iPLA2-VIA. In addition, rescue of phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration is observed, but a variant implicated in several PLA2G6-related diseases fails to rescue these phenotypes. Variant(s) implicated in human disease tested (as transgenic human gene, PLA2G6): the A80T variant form has been introduced into flies.
Animals homozygous for an amorphic mutation of iPLA2-VIA exhibit a reduced lifespan, acceleration of normal age-related locomotor impairment, and reduced fertility in females. Progressive degeneration in the adult brain, including degeneration of DA neurons, and progressive mitochondrial defects are observed; responses to various forms of stress are impaired. Bang-sensitivity is also observed. Genetic and physical interactions of Dmel\iPLA2-VIA have been described; see below and in the iPLA2-VIA gene report.
[updated Mar. 2020 by FlyBase; FBrf0222196]
Mutations in PLA2G6 are associated with multiple degenerative disorders.
Loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane abnormalities (Kinghorn et al., 2015; pubmed:26001724; FBrf0228781).
PLA2G6 encodes an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. [from Gene Cards, PLA2G6; 2016.04.11]
The endocytic membrane-trafficking pathway and disruption of synaptic vesicle endocytosis appear to play major roles in the risk of Parkinson disease. A substantial amount of genetic variation in PD and parkinsonism has been associated with vesicle trafficking via endosomal gene alterations. (Bandres-Ciga et al., 2019, pubmed:30675927; Nguyen et al., 2019, pubmed:30509690). Relevant genes include DNAJC6 (see FBhh0000594, FBhh0000593), SYNJ1 (see FBhh0000626), GAK (see FBhh0000593) and SH3GL2, which are linked to clathrin-coated vesicles, and VPS35 (see FBhh0000030) and DNAJC13 (see FBhh0001155), which participate in recycling components from the endosomes to the Golgi. In addition, LRRK2 (see FBhh0000011) and PLA2G6 (see FBhh0000243, FBhh0000232) have been shown to interact with genes involved in endocytic membrane trafficking.
One to one: 1 human to 1 Drosophila.
Ortholog of human PLA2G6 (1 Drosophila to 1 human). Dmel\iPLA2-VIA shares 35% identity and 53% similarity with human PLA2G6.