Age-dependent loss of dopaminergic neurons is the defining feature of Parkinson’s disease. Mutations and inactivation of parkin, an ubiquitin E3 ligase, induce Parkinson’s disease through accumulation of pathogenic substrates. The authors of this study report that overexpression of 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 (PARP1). AIMP2 accumulation resulted in PARP1 overactivation and dopaminergic cell toxicity via direct association of these proteins in the nucleus. Inhibition of PARP1 through gene deletion or drug inhibition reversed behavioral deficits and protected against dopamine neuron death in AIMP2 transgenic mice. The authors suggest that development of brain-permeable PARP inhibitors could be useful in delaying or preventing disease progression in Parkinson’s disease.
Lee Y, Karuppagounder SS, Shin JH, Lee YI, Ko HS, Swing D, Jiang H, Kang SU, Lee BD, Kang HC, Kim D, Tessarollo L, Dawson VL, Dawson TM: Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nature Neurosci. [Epub ahead of print, August 25, 2013; doi: 10.1038/nn.3500].