Figure 1.

Schematic illustration of gene-environment interactions impacting in mDA neuron survival/protection in the adult midbrain via Wnt1/β-catenin signaling. Major environmental factors including aging, inflammation, neurotoxin exposure including PD neurotoxins (MPTP/MPP+, 6-OHDA), pesticides (rotenone), increased oxidative load as a result of gowth factors (GFs) deprivation in synergy with genetic mutations (see Table 1), may antagonize Wnt/β-catenin signaling (“Wnt off ”) in mDA neurons. Up-regulation of active GSK-3β, then lead to β-catenin degradation and increased DA neuron vulnerability/degeneration/apoptosis. By contrast, in the intact midbrain canonical Wnt agonists, such as Wnt1, Rspo or Norrin, and activation of Fzd-1 receptors also via exogenous Wnt/β-catenin activation such as GSK-3β antagonist, NO-NSAIDs treatments tors (“Wnt on”), contribute to maintain the integrity of mDA neurons via blockade of GSK-3β-induced phosphorylation (P) and proteosomal degradation of the neuronal pool of β-catenin. Stabilized β-catenin can translocate into the nucleus and associate with a family of transcription factors and regulate the expression of Wnt target genes involved in DA neuron survival/plasticity, neuroprotection and repair. β-catenin may also function as a pivotal defense molecule against oxidative stress, and can act as a coactivator for several nuclear receptors involved in the maintenance/protection of DA neurons. The hypothetical contribution of various endogenous Wnt agonists (Respondin, Rspo, Norrin) or antagonists (Dkkopf, Dkk1, Wif, frizzled-related proteins, SFRp) are also indicated.