Parkinson’s disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc).  Using mice deficient in PitX3, a transcription factor critical for survival of mDA during development, flow cytometry and expression profiling was used to identify RGS6 for its restricted expression in these neurons.  In contrast to Pitx3-/- mDA neurons that die during fetal or postnatal periods, the mDA neurons of RGS6-/- mice begin to exhibit unilateral signs of degeneration in an age-dependent manner.  Unilateral cell loss is accompanied by contralateral degenerating neurons that show smaller cell size, altered morphology and reduced dendritic networks.  The degenerating neurons have low levels of tyrosine hydroxylase and Pitx3 and its target genes such as Vmat2, Bdnf, Aldh1a1, and express markers of increased dopaminergic signaling including dopamine transporter (DAT).  The late onset degeneration may reflect the protective action of RGS6 against excessive DA signaling throughout life.  RGS6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neruons that are most affected in PD.  This work thus indicates that RGS6 could be a new target in the development of drugs against PD.