Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.

The defining pathogenic feature of Parkinson's disease is the age-dependent loss of dopaminergic neurons. Mutations and inactivation of parkin, an ubiquitin E3 ligase, induce Parkinson's disease through accumulation of pathogenic substrates. We found that transgenic overexpression of a parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2), led to a selective, age-dependent, progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 AIMP2 accumulation in vitro and in vivo resulted in overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus, providing a path to Pduanyu371 activation other than DNA damage. Inhibition of Pduanyu371 through gene deletion or drug inhibition reversed behavioral deficits and protected against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain-permeable inhibitors could effectively delay or prevent disease progression in Parkinson's disease.

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