Role of Reactive Astrocytes and Microglia: Wnt/β-Catenin Signaling in Neuroprotection and Repair in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative pathology defined by specific, distinctive signs, primarily the progressive loss of dopaminergic neurons (DAergic) in the substantia nigra pars compacta (SNpc), associated with gliosis phenomena. The mechanisms that trigger the degeneration of DAergic neurons are not yet fully elucidated, although it is recognized that the interaction between genetic and environmental factors acts as a critical modulator of neuronal vulnerability. Strong evidence points to glial reactivity as a central element in PD pathophysiology; however, it remains a controversial topic whether this activation has a protective effect or, on the contrary, whether it contributes to exacerbating DAergic neuronal loss. The use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-a neurotoxic substance-represented a turning point in Parkinson's research, allowing the clarification of various molecular mechanisms of the disease. The primary aim of this review is to explore the current state of knowledge regarding the role of astrocytes in the processes of DAergic neurodegeneration, neuroprotection, and neurorepair. We focused on the relationship between astrocytic origin factors and neurogenic signals that mediate MPTP-induced plasticity in DAergic neurons of the nigrostriatal system. The contribution of reactive astrocytes in promoting DAergic neurogenesis starting from Neural Stem/Progenitor Cells (NPCs) present in the adult midbrain is also analyzed. Among the mediators released by astrocytes, we have previously identified the Wnt/β-catenin signaling pathway as a fundamental element capable of positively influencing neuroplasticity and dopaminergic neuronal repair induced by the toxic MPTP. In conclusion, deciphering the intrinsic plasticity of nigrostriatal DAergic neurons and signals that facilitate communication between astrocytes and NPCs is crucial for the identification of potential therapeutic targets aimed at stimulating neuronal repair.