Proposed mechanism for glial purinergic dysfunction leading to loss of myelination and cell death. In acute inflammation scenarios, microglial activation upregulates P2Y12 receptor expression and activity (blue), stimulating microglial motility to the injury site. The activation of these receptors reduces P2Y1 receptor (red) expression in astrocytes, increasing reactive astrogliosis and promoting neuroprotection. Chronic inflammation, as observed in motor neuron diseases (MND), unable of upregulating microglial P2Y12 receptor expression results in constant astrocytic P2Y1 receptor activation and reduction of A1 receptor expression (yellow). These events result in stimulating tumour necrosis factor α (TNF-α) release, which in turn induces A2B receptor activation (orange) and release of IL-6. These detrimental factors induce oligodendrocyte death and neuron demyelination, aggravating the pathological scenario