Physiopathological Protein Release by Glial Cells: Focus on Purine Nucleoside Phosphorylase (PNP), Superoxide Dismutase 1 (SOD1) and α-Synuclein.

The interest on Purine Nucleoside Phosphorylase (PNP), Superoxide Dismutase 1 (SOD1) and α-synuclein derived from the fact that they are all involved in brain neuropathology.Mutations in the gene codifying for PNP induce PNP deficiency, a neurodevelopmental disorder characterized by immunodeficiency; SOD1 and alpha-synuclein are involved in amyotrophic lateral sclerosis and Parkison’s disease respectively, both characterized by the presence of protein aggregates, neurodegeneration and neuroinflammation. Because in all these neurological diseases there is a strong involvement of immune cells, we focused on the role of glial cell secretion. Here we obtained data on PNP release by glial cells and we could speculate that, by releasing this enzyme, these cells may support neuronal activity, by maintaining the homeostasis of the purinergic system. In particular, since cerebellar neurons displayed a low content and reduced capability of releasing PNP, we hypothesize that glial PNP is particularly important for their function. By using in vitro models of rat primary cultures of glial cells overexpressing wt or mutated SOD1, we observed that SOD1 carrying the mutations linked to fALS is less released than wild-type and accumulates intracellularly promoting the autophagy impairment and in turn, glial activation that might be responsible for reduced neuroprotection against glutamate excitotoxicity in co-cultures with cerebellar granule neurons. Trehalose seems to restore the physiological expression and release of mutant SOD1, as well as the physiological neuroprotective role of microglia. Astrocytes seem to be less susceptible to overexpression of mutated SOD1. α-synuclein carrying the mutations linked to familial forms of PD is more released than wild-type, in accordance to the increased release promoted by activated glial cells. The increased toxicity due to overexpression of mutant α-synuclein together with the increased release might be responsible for reduced neuroprotection and for the diffusion of potential toxic molecules support the prion-like hypothesis for Parkinson’s Disease.