The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets

Nat Cell Biol. 2023 Aug;25(8):1101-1110. doi: 10.1038/s41556-023-01178-w.

Jeeyun Chung ¹ ² ³, Joongkyu Park ⁴, Zon Weng Lai ¹ ², Talley J Lambert ¹ ⁵, Ruth C Richards ¹ ², Jiuchun Zhang ¹, Tobias C Walther ^# ⁶ ⁷ ⁸ ⁹ ¹⁰, Robert V Farese Jr ^# ¹¹ ¹² ¹³ ¹⁴

Affiliations

1 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
2 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
3 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
4 Department of Pharmacology, Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
5 Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
6 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. twalther@mskcc.org.
7 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. twalther@mskcc.org.
8 Broad Institute of Harvard and MIT, Cambridge, MA, USA. twalther@mskcc.org.
9 Howard Hughes Medical Institute, Boston, MA, USA. twalther@mskcc.org.
10 Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. twalther@mskcc.org.
11 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. rfarese@mskcc.org.
12 Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. rfarese@mskcc.org.
13 Broad Institute of Harvard and MIT, Cambridge, MA, USA. rfarese@mskcc.org.
14 Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rfarese@mskcc.org.
# Contributed equally.

PMID: 37443287 DOI: 10.1038/s41556-023-01178-w

Abstract

Lipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular mechanisms mediating LD degradation by selective Autophagy (lipophagy) are unknown. Here we identify spartin as a receptor localizing to LDs and interacting with core Autophagy machinery, and we show that spartin is required to deliver LDs to lysosomes for triglyceride mobilization. Mutations in SPART (encoding spartin) lead to Troyer syndrome, a form of complex hereditary spastic paraplegia¹. Interfering with spartin function in cultured human neurons or murine brain neurons leads to LD and triglyceride accumulation. Our identification of spartin as a lipophagy receptor, thus, suggests that impaired LD turnover contributes to Troyer syndrome development.

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