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

• Published in: Nanomedicine 2020-02, Vol.24, p.102088-102088, Article 102088
• Main Authors: Sardoiwala, Mohammed Nadim, Srivastava, Anup K., Kaundal, Babita, Karmakar, Surajit, Choudhury, Subhasree Roy
• Format: Article
• Language: English
• Subjects: EZH2; Metformin loaded polydopamine nanoparticle; Parkinson’s disease; pSer129 α-synuclein; Ubiquitination
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2019.102088

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. Metformin nanoformulation [Metformin loaded Polydopamine nanoparticles] being synthesized by solution oxidation mediated self-assembly of dopamine molecules. Rotenone exposure inhibit ETC complex I of SH-SY5Y cells, thus depletion of ATP leads to simulate PD effect [in vitro PD model (1D and 3D raft PD model, PD model of mouse brain slice culture)] . Treatment of Metformin nanoformulation reduced inhibitory effects of rotenone and rescue dopaminergic neuronal cell model [SH-SY5Y cells] from apoptosis by inhibiting CASPASE3, α-Syn and 3PK and upregulating TH, DRD3, PP2A, BMI1 and novel PD associated therapeutic target EZH2. This molecular insight into the neuroprotective action of metformin nanoformulation has confirmed excellent neuroprotective potential of metformin and polydopamine nanoparticles in a signal platform as metformin nanoformulation in treatment of PD. [Display omitted]