Neuroprotection targeting mitochondrial dysfunction has been proposed as an important therapeutic strategy for Parkinson’s disease.Ganoderma lucidum (GL) has emerged as a novel agent that protects neurons from oxidative stress.However,the detailed mechanisms underlying GL-induced neuroprotection have not been documented.In this study,we investigated the neuroprotective effects of GL extract (GLE) and the underlying mechanisms in the classic MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD.Mice were injected with MPTP to induce parkinsonism.Then the mice were administered GLE (400 mg kg-1d-1,ig) for 4 weeks.We observed that GLE administration significantly improved locomotorperformance and increased tyrosine hydroxylase expression in the substantia nigra pars compact (SNpc) of MPTP-treated mice.In in vitro study,treatment of neuroblastoma neuro-2a cells with 1-methyl-4-phenylpyridinium (MPP+,1 mmol/k) caused mitochondrial membrane potential collapse,radical oxygen species accumulation,and ATP depletion.Application of GLE (800 μg/mL) protected neuroblastoma neuro-2a cells against MPP+ insult.Application of GLE also improved mitochondrial movement dysfunction in cultured primary mesencephalic neurons.In addition,GLE counteracted the decline in NIX (also called BNIP3L) expression and increase in the LC3-Ⅱ/LC3-1 ratio evoked by MPP+.Moreover,GLE reactivated MPP+-inhibited AMPK,mTOR,and ULK1.Similarly,GLE was sufficient to counteract MPP+-induced inhibition of PINK1 and Parkin expression.GLE suppressed MPP+-induced cytochrome C release and activation of caspase-3 and caspase-9.In summary,our results provide evidence that GLE ameliorates parkinsonism pathology via regulating mitochondrial function,autophagy,and apoptosis,which may involve the activation of both the AMPK/mTOR and PINK1/Parkin signaling pathway.