Poly-γ-glutamic acid alleviates cytotoxicity and inflammation induced by pre-formed fibrils of α-synuclein in murine primary astrocytes

Poly-γ-glutamic acid (γ-PGA) is a bacterial-derived natural biopolymer that has gathered significant interest due to its antioxidant, anti-inflammatory, and neuroprotective properties. These characteristics make γ-PGA a potential candidate for the treatment of neurodegenerative diseases. In Parkinson's disease (PD), whose key pathological feature is the accumulation of neuronal α-synuclein aggregates, astrocytes, in addition to microglia, play a crucial role in clearing these aggregates; however, their capacity is limited. Overwhelmed astrocytes trigger an inflammatory response that exacerbates neurodegeneration. Therefore, strategies aimed at regulating the uptake of extracellular α-synuclein aggregates by astrocytes and mitigating inflammation could hold therapeutic promise. This work aimed to investigate the potential of γ-PGA in preventing or reversing the toxicity and inflammatory response induced by pre-formed α-synuclein fibrils (PFFs) in murine cortical astrocytes. Cell viability assays demonstrated that γ-PGA can counteract the toxicity induced by α-synuclein PFFs. Confocal microscopy and 3D reconstruction analyses revealed that γ-PGA colocalizes with PFFs, leading to a reduction in the uptake of these aggregates by astrocytes and a subsequent decrease in their inflammatory response. Consequently, γ-PGA emerges as a promising candidate for further investigation in the therapeutic management of PD.