{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DDHD2 is a member of the intracellular phospholipase A1 (iPLA1) family that plays a critical role in lipid metabolism and membrane homeostasis. In the central nervous system its enzymatic activity is essential for the hydrolysis of triglycerides and phospholipids, thereby regulating neuronal lipid droplet turnover and preventing ectopic lipid accumulation. Loss‐of‐function mutations that disrupt DDHD2’s phospholipase activity have been causatively linked to SPG54, a form of complex hereditary spastic paraplegia characterized by early onset spastic paraplegia, intellectual disability, and distinctive brain imaging abnormalities including abnormal lipid peaks on MR spectroscopy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its neuroprotective functions, DDHD2 has been implicated in oncogenesis. Genomic studies of breast cancer have revealed that DDHD2 can be amplified and overexpressed, where it appears to cooperate with oncogenic drivers such as MYC to promote tumorigenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, its phospholipase activity depends on specific domains—including a DDHD domain critical for catalytic function and a sterile alpha motif implicated in phosphoinositide binding and membrane targeting—as shown by domain deletion and mutational analyses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent genome‐wide association and functional studies have expanded the relevance of DDHD2 to neurodevelopmental disorders, with risk alleles associated with decreased DDHD2 expression found in autism spectrum disorder."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In parallel, DDHD2 has been identified as possessing diacylglycerol lipase activity in the brain, further underscoring its role in neuronal glycerolipid metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cancer context, regulatory networks involving non‐canonical miRNA targeting also implicate DDHD2. For example, miR‑503 has been shown to repress DDHD2 expression via pairing outside the canonical seed region, suggesting that dysregulation of this interaction may contribute to breast cancer tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Additionally, in papillary thyroid cancer, the oncogenic circular RNA circRUNX1 modulates disease progression through a miR‑296‑3p/DDHD2 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies establish DDHD2 as a multifunctional lipid hydrolase whose activity is central to maintaining neuronal lipid homeostasis and whose disruption contributes to neurodegenerative as well as oncogenic processes. Its emerging roles in diverse pathological contexts underscore the potential benefits of targeting DDHD2-mediated pathways for therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Janneke H M Schuurs-Hoeijmakers, Michael T Geraghty, Erik-Jan Kamsteeg, et al. 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