A Self-Assembled α-Synuclein Nanoscavenger for Parkinson’s Disease

Abstract

Although emerging evidence suggests that the pathogenesis of Parkinson’s disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.

Trojan Horse Delivery of 4,4′‐Dimethoxychalcone for Parkinsonian Neuroprotection

“…[ 17,18 ] Appropriation of brain‐targeting ligands, such as transferrin receptors and glucose transporters, facilitates BBB penetration by nanodelivery systems for more effective neurodegenerative diseases therapy. [ 19,20 ] Although several systems have been established to delivery nanomedicines that target α ‐synuclein, as another pathological hallmark in PD progression, [ 20,21 ] targeted delivery systems to treat PD by restoring DA activity remain unexplored.…”

Curcumin Formulations and Trials: What’s New in Neurological Diseases

“…Recently, Liu et al developed an intranasal delivery system for the brain-targeted delivery of a curcumin analogue-based nanoscavenger (curcumin analogue molecules with polyethylene glycol). The authors showed that this treatment stimulated nuclear translocation of transcription factor EB, one of the major autophagy regulators, thereby triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-Syn [66]. Finally, chronic and acute curcumin treatment of transgenic mice overexpressing GFP-tagged wild-type α-Syn improved motor behavior, which was correlated with an increase in phosphorylated α-Syn protein in the cortical presynaptic terminals [67].…”

“…It has been demonstrated that curcumin regulates the early aggregation phases of reduced superoxide dismutase 1 (SOD1), one of the main proteins associated with Amyotrophic Lateral Sclerosis (ALS), leading to the production of non-fibrillar smaller and less toxic aggregates [66]. It also binds these products strongly, blocking their aggregation sites and, thus, inhibits the production of toxic species [68].…”

Curcumin in antidepressant treatments: An overview of potential mechanisms, pre‐clinical/clinical trials and ongoing challenges

“…Various nanomedicine strategies, such as solid lipid nanoparticles, polymeric micelles, nano-emulsions and nanosuspensions/nanocrystals, have been recently exploited for effectively circumventing the delivery limitations of curcumin. [128][129][130] For instance, curcumin encapsulated in poly (lactic-coglycolic acid) nanoparticles not only offers significantly better BBB penetration in rat models but also shows longer retained time in the cerebral cortex and hippocampus when compared with that of curcumin molecules. 131 Besides, He et al 132 applied solid lipid nanoparticles to co-load HU-211 and curcumin that can deliver more curcumin to the brain and increase the neurotransmitter level in brain tissue.…”