Recuperative effect of metformin loaded polydopamine nanoformulation promoting EZH2 mediated proteasomal degradation of phospho-α-synuclein in Parkinson’s disease model

Posttranslational modification and agglomeration of α-synuclein (α-Syn), mitochondrial dysfunction, oxidative stress and loss of dopaminergic neurons are hallmark of Parkinson's disease (PD). This paper evaluates neuroprotection efficacy of nature inspired biocompatible polydopamine nanocarrier for metformin delivery (Met encapsulated PDANPs) by crossing blood brain barrier in in vitro, 3D and in vivo experimental PD models. The neuroprotective potential was arbitrated by downregulation of phospho-serine 129 (pSer129) α-Syn, with reduction in oxidative stress, prevention of apoptosis and anti-inflammatory activities. The neuroprotective mechanism proved novel interaction of epigenetic regulator EZH2 mediated ubiquitination and proteasomal degradation of aggregated pSer129 α-Syn. In summary, this study divulges the neuroprotective role of Met loaded PDANPs by reversing the neurochemical deficits by confirming an epigenetic mediated nanotherapeutic approach for the PD prevention.