Objective: This study aims to elucidate the regulatory role of stearoyl-CoA desaturase 1 (SCD1) in Parkinson’s disease (PD)-associated intestinal dysfunction, focusing on its mechanism in lipid droplet (LD)-palmitic acid (PA) metabolic imbalance and downstream inflammatory signaling.

Background: Growing evidence highlights intestinal dysfunction as a critical contributor to PD pathogenesis. Previous work by our team identified lipid metabolic reprogramming in PD patients as closely linked to intestinal pathology, yet the molecular pathways remained undefined.

Method: Targeted metabolomics was used to detect serum lipid metabolism profile characteristics of PD. We used lipidomics, palmitoylation analysis, Nur77 mitochondrial translocation, protein post-translational modification analyses in enteric glial cells (EGCs) of PD A53T α-synuclein transgenic (Tg) mice and IEC-CS co-cultured with EGCs as in vitro model of the intestinal dysfunction of PD.

Results: The metabolomics of PD patients showed lipid disorder, decreased PA level and negative correlation with PD disease severity. Notably, abnormal LD accumulation in enteric glial cells (EGCs), reduced PA levels, and elevated interleukin-6 in vivo/vitro PD intestinal dysfunction models. Further experiments revealed that in vivo/vitro PD intestinal dysfunction models, SCD1 overexpression in EGCs induced LD accumulation via enhanced desaturation activity, which sequestered PA into LDs. Reduced PA availability impaired ZDHHC20-mediated S-palmitoylation of Nur77, hindering its mitochondrial translocation and causing mitophagy dysfunction. Mitophagy defects activated the IL-6/IL-6R pathway in intestinal epithelial cells, establishing a glial-epithelial inflammatory feedback loop. SCD1 inhibition reversed PA sequestration, restored Nur77 palmitoylation, and suppressed IL-6-driven inflammation, confirming its central role.

Conclusion: This study unveils a novel “SCD1-LD/PA-Nur77-IL-6” axis regulating PD-associated intestinal dysfunction. By integrating perspectives on LD dynamics, post-translational modifications, and glial-epithelial crosstalk, these findings provide novel therapeutic strategies for targeted intervention in PD’s gut-brain axis.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/fatty-acid-metabolic-reprogramming-regulates-glial-epithelial-axis-via-nur77-palmitoylation-in-intestinal-dysfunction-in-parkinsons-disease/