| First Author | Shaltiel-Karyo R | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 24 | Pages | 17579-88 |
| PubMed ID | 23637226 | Mgi Jnum | J:199598 |
| Mgi Id | MGI:5503268 | Doi | 10.1074/jbc.M112.434787 |
| Citation | Shaltiel-Karyo R, et al. (2013) A blood-brain barrier (BBB) disrupter is also a potent alpha-synuclein (alpha-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD). J Biol Chem 288(24):17579-88 |
| abstractText | 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 alpha-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 alpha-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 alpha-synuclein from alpha-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 alpha-synuclein aggregates in the brains of treated flies. In the mThy1-human alpha-synuclein transgenic mouse model, a decrease in alpha-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes alpha-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. |
