The Inherent Distinction Among DA Neurons In C.elegans Determines The Human TRPM2 Selectively Inducing ADE Degeneration

Parkinson’s disease is one of the most threatening neurodegenerative disorders which cause severe dopaminergic neurodegeneration in the substantia nigra pars compacta（SNc）while dopamine neurons in the ventral tegmental area（VTA）are much less affected.Here we revealed that non-selective cation channel TRPM2 played an important role in PD via h TRPM2 transgenic strain of C.elegans.The transgenic worm suffered selectively ADE dopaminergic neurons death within seven days while CEP,another kind of dopamine neurons kept intact,similar to the VTA dopamine neuron.We also proved that the degeneration of ADE neuron conducted a non-canonical death pathway in which ced-9 plays a central but non-canonical role through disturbing mitochondrial dynamics,Ca²⁺imbalance and ROS also participated in ADE death,while CEP neurons may survived for lower PARP-1 and ADPR production,for PARP-1overexpression aggravating ADE death and lead to extra CEP death.Besides,the results of single-cell sequencing help to demonstrate the inherent difference of ADE and CEP,and the expression level of genes concerning about regulating nitric oxide synthesis（higher in ADE）and catabolism（lower in ADE）may be the fundamental difference between ADE and CEP.PD patients-specific induced pluripotent stem cells derived DA neurons also demonstrated the abnormal mitochondria and lower expression levels of PARP-1,which proved,to some extent,the PARP-1/TRPM2 axis in worms mediating the DA neurons degeneration and the difference between different subpopμLation of dopamine neurons might are conserved（data not shown）.