Activating mitochondrial regulator PGC-1α expression by astrocytic NGF is a therapeutic strategy for Huntington's...

Mitochondrial dysfunction plays an important role in Huntington's disease (HD). NGF gene delivery in AD patients showed an increase in brain energy metabolism and NGF has been shown neuroprotective effects against mitochondrial toxins. However, the role of NGF in regulating mitochondrial function is unclear. Here, we found that NGF-stimulated mitochondrial biogenesis in PC12 and primary neuron cells. Our results demonstrated that peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) is a downstream key target of the NGF signalling pathway. In a 3-nitropropionic acid (3-NP) cell model, NGF treatment rescued the defects in mitochondrial activity and mitochondrial membrane potential. Since NGF cannot freely cross blood-brain barrier, we found an astrocytic NGF inducer, Ganoderma lucidum (GaLu) extract. Its active constituents had potent effects on the induction of NGF in primary astrocytes. Among the identified ingredients, ganoderic acid C₂ was most effective. We further found that GaLu-conditioned media can enhance mitochondrial biogenesis in PC12 cells and preventing NGF signalling using NGF antibody or PGC-1α siRNA blocked these effects. Moreover, GaLu and ganoderic acid C₂-conditioned media treatment attenuated mitochondrial defects in 3-NP cell model. After 3-NP-induced behavioural impairment and striatal degeneration in mice, GaLu treatment therapeutically restored the behaviour score, sensorimotor ability and neuronal loss. We found that striatal NGF, PGC-1α expression level and succinate dehydrogenase activity were recovered in GaLu-fed mice. These results suggest that the NGF-signalling pathway connected to the mitochondrial regulator, PGC-1α, expression. This signalling triggered by astrocytic NGF with small molecule inducers may offer a therapeutic strategy for HD.