FGF21 confers neuroprotection in Parkinson’s disease by activating the FGFR1-sirt1 pathway

Parkinson’s disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear. Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms. FGF21OE significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood–brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways. FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival. FGF21 has a significant impact on PD and exerts its effects through the FGFR1-Sirt1 pathway and others. Proteins related to the BBB (claudin, occludin, ZO-1) and astrocytes (GFAP) are involved. After FGF21 binds to FGFR1, it activates the Sirt1 pathway to regulate mitochondrial dynamics (promoting fusion and inhibiting fission), and activates the AMPK pathway to regulate autophagy and inhibit apoptosis. In addition, FGF21 can also induce the transformation of M1 microglia into M2 microglia. In summary, through multiple signaling pathways, FGF21 regulates mitochondria, microglia, autophagy, apoptosis, and neuronal survival in PD.