Molecular basis of unique specificity and regulation of group VIA calcium-independent phospholipase A (PNPLA9) and its role in neurodegenerative diseases.

Glycerophospholipids are major components of cell membranes and consist of a glycerol backbone esterified with one of over 30 unique fatty acids at each of the sn-1 and sn-2 positions. In addition, in some human cells and tissues as much as 20% of the glycerophospholipids contain a fatty alcohol rather than an ester in the sn-1 position, although it can also occur in the sn-2 position. The sn-3 position of the glycerol backbone contains a phosphodiester bond linked to one of more than 10 unique polar head-groups. Hence, humans contain thousands of unique individual molecular species of phospholipids given the heterogeneity of the sn-1 and sn-2 linkage and carbon chains and the sn-3 polar groups. Phospholipase A (PLA) is a superfamily of enzymes that hydrolyze the sn-2 fatty acyl chain resulting in lyso-phospholipids and free fatty acids that then undergo further metabolism. PLA's play a critical role in lipid-mediated biological responses and membrane phospholipid remodeling. Among the PLA enzymes, the Group VIA calcium-independent PLA (GVIA iPLA), also referred to as PNPLA9, is a fascinating enzyme with broad substrate specificity and it is implicated in a wide variety of diseases. Especially notable, the GVIA iPLA is implicated in the sequelae of several neurodegenerative diseases termed "phospholipase A-associated neurodegeneration" (PLAN) diseases. Despite many reports on the physiological role of the GVIA iPLA, the molecular basis of its enzymatic specificity was unclear. Recently, we employed state-of-the-art lipidomics and molecular dynamics techniques to elucidate the detailed molecular basis of its substrate specificity and regulation. In this review, we summarize the molecular basis of the enzymatic action of GVIA iPLA and provide a perspective on future therapeutic strategies for PLAN diseases targeting GVIA iPLA.