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, cause Parkinson’s disease through accumulation of pathogenic substrates. Here we show that transgenic overexpression of the parkin substrate, aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2) leads to a selective, age-dependent progressive loss of dopaminergic neurons via activation of poly(ADP-ribose) polymerase-1 (PARP1). AIMP2 accumulation in vitro and in vivo results in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus providing a new path to PARP1 activation other than DNA damage. Inhibition of PARP1 through gene deletion or drug inhibition reverses behavioral deficits and protects in vivo against dopamine neuron death in AIMP2 transgenic mice. These data indicate that brain permeable PARP inhibitors could be effective in delaying or preventing disease progression in Parkinson’s disease.