Pla2g6, the phospholipase A2 group VI gene, encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α -synuclein aggregation [1]. The enzyme belongs to the PLA2 superfamily, hydrolyzing the sn-2 ester bond in phospholipids, and is essential for remodeling membrane phospholipids in axons and synapses within the nervous system [2].

In the Pla2G6 knockout (KO) mouse, which serves as an excellent model for studying Pla2G6-associated neurodegeneration (PLAN), specific membrane degeneration occurs in neurons and their axons, followed by axonal spheroid formation. From a young age, many mitochondria with damaged inner membranes appear in Pla2G6 KO mouse neurons. These injured mitochondria move anterogradely within the axons, accumulating in the distal axons. As membrane degeneration progresses, the double-membrane of mitochondria collapses, accompanied by axonal injury near impaired mitochondria. At the axon terminals, the presynaptic membranes expand irregularly from a young age and eventually rupture, causing axon terminal degeneration [2].

In conclusion, Pla2g6 is crucial for maintaining membrane integrity in neurons, especially in mitochondria and axon terminals. The Pla2G6 KO mouse model has revealed that defective membrane maintenance due to Pla2g6 deficiency may underlie the pathologies of PLAN, Parkinson disease, and neurodegeneration with iron accumulation (NBIA), which are associated with primary axonal degeneration [2].

References:

1. Deng, Xinyue, Yuan, Lamei, Jankovic, Joseph, Deng, Hao. 2023. The role of the PLA2G6 gene in neurodegenerative diseases. In Ageing research reviews, 89, 101957. doi:10.1016/j.arr.2023.101957. https://pubmed.ncbi.nlm.nih.gov/37236368/

2. Sumi-Akamaru, Hisae, Beck, Goichi, Kato, Shinsuke, Mochizuki, Hideki. 2015. Neuroaxonal dystrophy in PLA2G6 knockout mice. In Neuropathology : official journal of the Japanese Society of Neuropathology, 35, 289-302. doi:10.1111/neup.12202. https://pubmed.ncbi.nlm.nih.gov/25950622/