A Blood-Brain Barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: A novel dual mechanism of mannitol for the treatment of Parkinson Disease (PD)

Ronit Shaltiel-Karyo, Moran Frenkel-Pinter, Edward Rockenstein, Christina Patrick, Michal Levy-Sakin, Abigail Schiller, Nirit Egoz-Matia, Eliezer Masliah, Daniel Segal*, Ehud Gazit

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.

Original languageAmerican English
Pages (from-to)17579-17588
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number24
DOIs
StatePublished - 14 Jun 2013
Externally publishedYes

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