Glia as a turning point in the therapeutic strategy of Parkinson's disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the presence of tremor, muscle rigidity, slowness of voluntary movements and postural instability. One of the pathological hallmarks of PD is loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). The cause and mechanisms underlying the demise of nigrostriatal DAergic neurons are not fully understood, 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, but whether astroglia activation may protect or exacerbate DAergic neuron loss is the subject of much debate. Astrocytes and microglia are the key players in neuroinflammatory responses, secreting an array of pro- and anti-inflammatory cytokines, anti-oxidants and neurotrophic factors. These mediators act as double-edged swords, exerting both detrimental and neuroprotective effects. Here, the contribution of astrocytes and microglia in mediating the effects of both genetic and environmental factors, including hormones, endotoxins and neurotoxins, and their ability to influence DAergic neurodegeneration, neuroprotection and neurorepair will be discussed. Approaches capable to regulate glial-associated oxidative stress and mitochondrial damage, by decreasing inflammatory burden, restoring mitochondrial function and DAergic neuron metabolism, might hold great promise for therapeutic interventions. Therapies that support astrocyte function, replacing astrocytes either modified or unmodified in culture, may represent novel approaches targeting astrocytes to promote DAergic neurorescue. Dissecting the molecular determinants of glia-neuron crosstalk will give us the possibility to test novel strategies to promote restoration of injured nigrostriatal DAergic neurons.