DDHD domain-containing lipases: Targets for the treatment of rare diseases

Abstract

The DDHD domain-containing lipases belong to the intracellular phospholipase A1 (iPLA1) family. Phospholipases have been implicated in the regulation of lipid metabolism, intracellular membrane trafficking, and signaling. In addition, phospholipases have been linked to the development of rare and neurodegenerative diseases. The rare and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease have been focused on phospholipase A2. But there is a scarcity of literature on the role of PLA1 in rare and neurodegenerative diseases. Recently, in humans, mutation in DDHD1 and DDHD2 (iPLA1 members) has been identified as a cause of specific types of hereditary spastic paraplegia (HSP) termed as SPG28 and SPG54, respectively. Ddl1 (DDHD domain-containing lipase 1), a yeast homolog of human DDHD1/2, hydrolyzes cardiolipin (CL), phosphatidylethanolamine, and phosphatidylglycerol. Ddl1 has an important role in the mitochondrial phospholipids remodeling. Defects in phospholipids remodeling and mitochondrial functions have been implicated in the development of the Barth syndrome, HSPs, and other neurodegenerative disorders. Mutations in DDHD1 and DDHD2 produce DDL1-defective yeast strain like phenotypes (mitochondrial dysfunction and defects in lipid metabolism). Therefore, the DDL1-defective yeast could be a good model system to understand hereditary spastic paraplegia.