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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Acknowledgements
The graphical model image was generated by BioRender.com. We thank Prof. Cheng Luo (Shanghai Institute of Materia Medica) for kindly providing DC-LC3in-D5 compound. Prof. Wei Liu (Zhejiang University) for kindly providing GFP-mCherry-livedrop constructs.
Funding
This work was in part supported by the National Natural Science Foundation of China (No. 92357301, 32370726, 91957125, 81972396 to C.W. 31821002, 31930062 to S.Z., 92049301, 82050008 to B.L., 31970748 to Y.F), the State Key Development Programs of China (No. 2022YFA1104200 to C.W.; 2018YFA0800300 to S.Z), the Natural Science Foundation of Shanghai (No. 22ZR1406600 to C.W), Science and Technology Research Program of Shanghai (No. 9DZ2282100). Science and Technology Commission of Shanghai Municipality (22S11900100 to Y.F).
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C.W. conceived the study. F.J. and X.W. performed the experiments and data analyses. C.W., B.L., S.Z. and Y.F. analyzed and interpreted the data. B.L. provided LD·ATTEC compound. C.W. wrote the manuscript.
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Jia, F., Wang, X., Fu, Y. et al. DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins. Cell Death Differ 31, 348–359 (2024). https://doi.org/10.1038/s41418-024-01261-1
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DOI: https://doi.org/10.1038/s41418-024-01261-1