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.
Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
Sudarshan
S
Phani
Michael
M
Jablonski
Josh
J
Pelta-Heller
Jingli
J
Cai
Lorraine
L
Iacovitti
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D050483:Dopamine Plasma Membrane Transport Proteins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium