α-Synuclein and Glia in Parkinson's Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System?

Accumulation of α-synuclein (α-syn) species in dopaminergic neurons is one of the main hallmarks of Parkinson's disease (PD). Several factors have been associated with α-syn aggregation process, including an impairment of the proper protein degradation, which might drive the neurons toward an alternative and/or additional clearance mechanism that involves the release of undigested material from the cell. It has been reported that extracellular α-syn, released by stressed and/or degenerating neurons, might widely contribute to the neuronal toxicity and degeneration. Therefore, the uptake and clearance of misfolded/aggregated proteins is a key process to control extracellular deposition of α-syn aggregates, the spreading and progression of the disease. All the main brain cell types, neurons, astrocytes and microglia are able to internalize and degrade extracellular α-syn, however, glial cells appear to be the most efficient scavengers. Accumulating evidence indicates that the endocytosis of α-syn species might be conformation-sensitive, cell- and receptor-type specific, making the scenario highly complex. In this review, we will shed light on the different endocytosis mechanisms and receptors recruited for the uptake and clearance of pathological α-syn forms with a special focus on glial cells. Moreover, we will discuss how PD-related genes, in addition to α-syn itself, may alter the endo-lysosomal pathway causing an impairment of clearance, which, in turn, lead to accumulation of toxic species, dysfunctions of glia physiology and progression of the disease.