Glucosamine conjugated gold nanoparticles modulate protein aggregation induced autophagic neuronal cell death via regulation of intracellular Parkin homeostasis

Abstract

Recent studies have suggested that ∼ 25% of the brain glycogen is composed of glucosamine (Gln), though its role in maintaining the balance in nervous system is yet to be fully understood. Here, we have reported the synthesis and protective effect of glucosamine conjugated gold nanoparticles (Gln@CA-AuNP) on the oligomeric and fibrillar fraction of hen egg white lysozyme (HEWL). The synthesized Gln@CA-AuNP (∼ 30.1±3.7 nm) was characterized by different spectroscopy and microscopy techniques. The corresponding biophysical studies suggested that Gln@CA-AuNP could effectively inhibit the HEWLO formation and simultaneously, could restrict the nucleation step of protein aggregation. Studies carried out with human neuroblastoma cells (SH-SY5Y) suggested that Gln@CA-AuNP alleviated protein aggregation induced cell death via inhibition of oligomer formation (∼ 2.4 times), reduction of intracellular oxidative stress (∼ 3.6 times) by uplifting the mitochondrial health. The intracellular delivery of Gln was found to modulate cytosolic Parkin oxidation and restrict autophagic neuronal cell death as confirmed by western blot studies. Further, Gln@CA-AuNP has been found to enhance sulfated glycosaminoglycans (sGAGs) production which suggested its role in protecting the extracellular matrix (ECM) during protein aggregation induced toxicity. Also, neuronal synapse of the in vivo Caenorhabditis elegans model could be preserved with the pre-treatment of Gln@CA-AuNP. Overall, we predict that this approach of neuroprotection via simultaneous targeting of early and late aggregates may serve as a better therapeutic strategy for the treatment of neurodegenerative diseases.