ArticleCell death and differentiation2024
DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.
Article in Cell death and differentiation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Neurons run on fat.npj metabolic health and disease · 2026Article
- Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.Cell death discovery · 2026Review
- Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The Role of the Golgi Apparatus in Neurodegeneration.Sub-cellular biochemistry · 2026Review
- DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.bioRxiv : the preprint server for biology · 2025Article
- Targeted Degradation Technologies Utilizing Autophagy.International journal of molecular sciences · 2025Review
- Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.Journal of inherited metabolic disease · 2025Review
- Acute lipid droplet accumulation induced by the inhibition of the phospholipase DDHD2 does not affect the level, solubility, or phosphoserine-129 status of α-synuclein.Metabolic brain disease · 2025Article
- DDHD2 promotes lipid droplet catabolism by acting as a TAG lipase and a cargo receptor for lipophagy.Autophagy · 2024Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in the DDHD2 gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathway both contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.
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