This edition of the Paris Postdocs Seminar Series at Institut Pasteur will take place Tuesday, 26 March 2024, at 11:00 in the Jules Bordet meeting room (Metchnikoff Building).
Parkinson’s disease (PD) represents the most common age-related neurodegenerative movement disorder that is characterized by the progressive loss of midbrain dopaminergic neurons and aggregation of α-synuclein in neuronal cell bodies and axons. The gut-brain axis has increasingly been considered to play an important role in the onset and progression of PD. In vitro, in vivo and clinical data indicate that short-chain fatty acids (SCFAs) modulate immune cell function and α-synuclein accumulation that could ultimately be propagated from the gut to the brain via the enteric nervous system. Despite tremendous efforts, the role of SCFAs in inflammation and the pathogenesis of PD remains controversial. In fact, some studies show that SCFAs exacerbate gut inflammation in mouse colitis models. Moreover, PD patients with mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase often display gastrointestinal symptoms. Models of impaired glucocerebrosidase activity demonstrate dysfunction of the autophagic-lysosomal pathway, accumulation of α-synuclein and aberrant lipid metabolism. To dissect the role of SCFAs and potential interaction with GBA1-related genetic risk in immune cell function and α-synuclein pathology, we employed human induced pluripotent stem cell-derived macrophages and microglia from GBA1-PD patients and isogenic gene-corrected controls. Our results demonstrate that the SCFA butyrate increased cytokine secretion and promoted lipid storage in control macrophages and microglia. Macrophages and microglia with GBA1 mutations showed reduced cytokine secretion upon activation and decreased phagocytic capacity compared to isogenic controls. These results suggest that butyrate as well as GBA1 mutations alter key functions of peripheral and brain-resident immune cells. Given the known link between glucocerebrosidase and α-synuclein, ongoing work is addressing the interaction between genetic vulnerability and SCFAs on neuro-immune interactions and PD pathology using intestinal and midbrain organoids with immune cells.
Room: Jules Bordet
Address: 25 Rue du Docteur Roux, Paris, France