Objectives: Misfolding and aggregation of α-synuclein (α-syn) is the hallmark of Parkinson's Disease. Osmolytes, e.g. polyols, are small molecules which accumulate under stress conditions and stabilize protein structure, acting as 'chemical chaperones'. They may reduce protein misfolding and aggregation in neurodegenerative diseases. The sugar alcohol sweetener Mannitol is a non-metablolized FDA-approved osmotic diuretic agent that also has BBB disrupting properties. We examined its ability to interfere with the aggregation of α-syn in vitro and in vivo.
Methods & Results: Low concentrations of Mannitol (450 and 225 mM) inhibited the in vitro formation of α-syn fibrils. High concentrations (900 mM) significantly decreased formation of tetramers and high molecular weight oligomers, and shifted the secondary structure from α-helical to a different structure, suggesting alternative potential pathways for aggregation. Feeding α-syn expressing Drosophila, which serve as an established model for PD, with 75mM Mannitol dramatically corrected their behavioral defects and reduced the amount of α-syn aggregates in their brains. Daily injection (IP) of 1 g/kg Mannitol to mThy1-human α-syn transgenic mice caused a significant decrease of α-syn accumulation in several brain regions, suggesting that Mannitol promotes α-syn clearance from the cell bodies. Mannitol appears to have a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. No adverse effects were observed in control Mannitol-treated flies or mice.
Conclusions: We suggest that Mannitol has a dual therapeutic mechanism for the treatment of PD – a BBB disruptor that also serves by itself as a chemical chaperone correcting the pathogenic misfolding of α-syn.
