Nanoascorbate Promotes Clearance of Mutant Huntingtin Aggregates via Restoration of Blocked Autophagy

Impaired autophagy is a key contributor to aging and a variety of protein aggregation-linked neurodegenerative disorders. In this direction, autophagy modulation is emerging as a therapeutic approach to combat protein aggregation-related neuronal diseases. Herein, we report that nanoascorbate, a biocompatible polymeric nanoform of vitamin C, accelerates the clearance of mutant Huntingtin protein aggregates in HD150Q, the cellular model of Huntington’s disease by restoring blocked autophagy. We have confirmed that nanoascorbate induces autophagic flux in autophagy-compromised Huntington’s model cells bearing mutant Huntingtin aggregates, evident from the altered expression level of the characteristic autophagy marker protein LC3BII and rapid degradation of crucial cargo receptor SQSTM/p62. In addition, blockade of autophagy induction using a potent autophagy inhibitor causes depression/failure of clearance of protein aggregates by nanoascorbate, indicating that nanoascorbate induces autophagy-mediated degradation. Furthermore, nanoascorbate-mediated upregulation of autophagic flux is ROS- and glutathione reductase-dependent. A brief incubation of 3h with a low micromolar concentration of nanoascorbate has shown an average 90% clearance of high-molecular-weight soluble aggregate of neurotoxic mutant Huntingtin protein, within 2 days. Nanoascorbate is faster, and a low micromolar concentration is sufficient compared to a high molar concentration of trehalose, a conventional autophagy inducer, that achieves only an average of 38% degradation after 96 h of prolonged incubation. In general, induced HD150Q cells bearing neurotoxic polyglutamine aggregates are prone to rapid apoptotic death. Nanoascorbate rescues mutant huntingtin aggregate-bearing cells from apoptotic insult which is evident from the lowered expression of cleaved caspase-3 manifolds, after brief incubation with nanoascorbate. In addition, dietary supplementation of nanoascorbate has shown moderate improvement in motor activity, an increase in life span, and suppression of progressive polyQ-induced eye degeneration to some extent in the transgenic Drosophila model of Huntington’s disease. Our findings manifest the remarkable neurotherapeutic potential of the nanoform of ascorbate via autophagy modulation in autophagy-compromised conditions as well as a moderate neuroprotective effect in the transgenic Drosophila model of Huntington’s disease. In addition, the current study emphasizes that modulation of autophagy can be considered as a promising therapeutic approach for proteinopathy-related neurodegenerative diseases.