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Uncovering novel actors in astrocyte–neuron crosstalk in Parkinson's disease: the Wnt/β‐catenin signaling cascade as the common final pathway for neuroprotection and self‐repair

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neuronal cell bodies in the substantia nigra pars compacta and gliosis. The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are ill‐defined, but interactions between genes and environmental factors are recognized to play a critical role in modulating the vulnerability to PD. Current evidence points to reactive glia as a pivotal factor in PD pathophysiology, playing both protective and destructive roles. Here, the contribution of reactive astrocytes and their ability to modulate DAergic neurodegeneration, neuroprotection and neurorepair in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) rodent model of PD will be discussed in the light of novel emerging evidence implicating wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin signaling as a strong candidate in MPTP‐induced nigrostriatal DAergic plasticity. In this work, we highlight an intrinsic Wnt1/frizzled‐1/β‐catenin tone that critically contributes to the survival and protection of adult midbrain DAergic neurons, with potential implications for drug design or drug action in PD. The dynamic interplay between astrocyte‐derived factors and neurogenic signals in MPTP‐induced nigrostriatal DAergic neurotoxicity and repair will be summarized, together with recent findings showing a critical role of glia–neural stem/progenitor cell (NPC) interactions aimed at overcoming neurodegeneration and inducing neurorestoration. Understanding the intrinsic plasticity of nigrostriatal DAergic neurons and deciphering the signals facilitating the crosstalk between astrocytes, microglia, DAergic neurons and NPCs may have major implications for the role of stem cell technology in PD, and for identifying potential therapeutic targets to induce endogenous neurorepair.