The presymptomatic phase of Parkinson's disease (PD) is now recognized as a prodromal phase, with compensatory mechanism masking its progression and non-motor early manifestations, such as depression, cognitive disturbances and apathy. Those mechanisms were thought to be strictly dopamine-mediated until recent advances have shed light upon involvement of putative outside-basal ganglia, i.e. cortical, structures. We took advantage of our progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model to monitor whole genome transcriptional changes in several brain areas. Our data reveals that transcriptomic activity changes take place from early stages, suggesting very early compensatory mechanisms or pathological activity outside the basal ganglia, including the PFC. Specific transcriptomic changes occurring in the PFC of fully parkinsonian MPTP-treated macaques have been identified. Interestingly, a large part of these transcriptomic changes were also observed in human post-mortem samples of patients with neurodegenerative diseases analysed by quantitative PCR. These results suggest that the PFC is able to detect the progression of dopamine denervation even at very early time points. There are therefore mechanisms, within the PFC, leading to compensatory alterations and/or participating to pathophysiology of prodromal PD manifestations. © 2010 Elsevier Inc.