The Pathogensis Of Parkinson Disease In Caenorhabditis Elegans Caused By Nocardia Farcinica And Its Molecular Mechanism

Parkinson Disease(PD)is the second most common neurodegenerative disease in the world.Its main symptoms include a series of moter deficit,such as balance disorder,bradykinesia,rigidity and rest tremor,combined with a few non-motor symptoms of depression,apathy,anxiety,dementia and so on.Pathological manifestations of PD patients are the abnormal aggregation of α-synuclein in neurons and formation of Lewy body,which leads to loss of dopamine neurons in substantia nigra and striatum,and futher decrease of dopaminergic signal.In terms of etiology,it is currently believed that aging,genetics and environment are the most important risk factors for PD.However,more and more experimental evidences also indicate that the involvement of microbial infection in PD occurrence,but its epidemiology and pathogenesis remain controversial.Recent studies have suggested that pathologic diffusion of PD during infection begins in the olfactory bulb and gastrointestinal peripheral nerves.Nocardia farcinica(N.farcinica)is an opportunistic pathogen that can cause infection of the central nervous system as well as the lung and some other peripheral systems.Some studies have also shown that the fermentation products of N.farcinica have the neurotoxic effects on dopamine neurons.However,the relationship between N.farcinica and PD pathogenesis remains not clear.Meanwhile,the key virulence factors and the detailed molecular mechanisms of pathogenesis require further elucidated.Therefore,using the model of Caenorhabditis elegans(C.elegans)as the research object,we here investigated the PD pathogenesis when N.farcinica intestinally infected C.elegans.It was found that the dopaminergic neurons had a lower GFP intensity and exhibited a loss of neuron integrity in C.elegans,and the axons broken or appeare blebbing;the basal slowing rate and bodybends reduced;the abnormal aggregation of α-synuclein,proving that infection of N.farcinica leads to PD pathogenesis of C.elegans in pathological features and clinical manifestations.In order to further identify the virulence factor of N.farcinica as well as its pathogenic mechanism,we successfully knocked out the salicylic acid synthetase gene nbt S responsible for the biosynthesis of nocobactin,which had been described a key virulence factor in the infection of N.farcinica.Then the pathogenicity of Δnbt S mutant was compared with that of the wild strain,and it was found that the gene deletion of nbt S could significantly weaken the pathogenicity of PD in C.elegans.In addition,the infection of N.farcinica could also induce the increase of ROS,disturbance of mitochondrial biomass,decrease of mitochondrial membrane potential and ATP content,and imbalance of mitochondrial fission and fusion.Furthermore,the mutant of Δnbt S partially rescued a series changes of mitochondrial function in C.elegans,suggesting that the mitochondrial dysfunction caused by N.farcinica should be an important strategy of PD pathogenesis of C.elegans.