Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss

Abstract

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.

Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration

“…IHC was performed as described previously (26,56). Mice were intracardially perfused with ice-cold PBS and 4% paraformaldehyde/PBS (wt/vol, pH 7.4) after deep anesthesia by i.p.…”

FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration

“…30,39,43 This study shows that FAF1 is essential for PARP1-dependent necrosis in response to oxidative stress, in which caspases are not activated. However, caspase-mediated apoptosis has also been found to occur in relation to the pathogenesis of PD, and the oxidative stress-induced damage in a mouse model of PD has been found to be reduced by treatment with caspase inhibitors, suggesting that caspase inhibition is also a plausible strategy for PD treatment.…”

“…The PARP1 activity can be regulated by the physical interaction of PARP1 with its binding partner. 39,40 Given that FAF1 interacts with PARP1, we examined whether the PARP1 activity might be regulated by FAF1. We found that FAF1 overexpression induced a dose-and timedependent increase in the PAR polymer in response to Figure S6a).…”

“…However, some proteins, such as aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) and glyceraldehyde-3-phosphate FAF1 acts as a parthanatos mediator C Yu et al dehydrogenase (GAPDH), activate PARP1 through physical interactions. 39,40 FAF1 also promotes the catalytic activity of PARP1 through physical interactions. FAF1 has several protein interaction domains that would facilitate the formation of a multiprotein complex.…”

“…Subcellular fractionation was performed as described by Lee et al,39 with some modifications. In brief, MEF or SH-SY5Y cells were suspended in a hypotonic buffer (10 mM HEPES, pH 7.5, 10 mM KCl, 1.5 mM MgCl 2 , 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.1% NP-40 and a protease inhibitor cocktail) and homogenized by passage through a 26 gauge syringe needle 20 times.…”