Gremlin is a novel VTA derived neuroprotective factor for dopamine neurons

Parkinson's disease and its characteristic symptoms are thought to arise from the progressive degeneration of specific midbrain dopamine (DA) neurons. In humans, DA neurons of the substantia nigra (SN) and their projections to the striatum show selective vulnerability, while neighboring DA neurons of the ventral tegmental area (VTA) are relatively spared from degeneration. Recent studies from our laboratory have shown that the VTA exhibits a unique transcriptional response when exposed to MPTP (Phani et al., 2010), a neurotoxin able to mimic the selective cell loss observed in PD (Schneider et al., 1987). In this study, we focus on gremlin, a peptide that is transcriptionally increased in the VTA in response to MPTP. We describe a novel role for gremlin as a neuroprotective agent both in vitro and in vivo and show that gremlin is capable of protecting SN DA neurons and several DA cell lines against MPP+/MPTP. We propose that this protection is mediated by VEGFR2, and by the MAP kinase signaling pathway downstream of the receptor. Our data indicate that gremlin may be a key factor in protecting the VTA against MPTP-induced cell death, and that exogenous application of gremlin is capable of protecting SN DA neurons, and therefore may provide an opportunity for the development of novel PD therapeutic compounds.