Therapeautic effects of FTY720 compounds in cellular and animal models of multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a rapidly progressing and fatal demyelinating neurodegenerative disorder with no effective treatment. MSA is characterized by the toxic accumulation of the protein alpha-synuclein (aSyn) inside oligodendroglia (OLG), the myelinating cells of the brain. We corroborated reports that aSyn accumulation inside OLG cells decreases expression of brain-derived neurotrophic factor (BDNF), a potent neuroprotective molecule. We further found that treating OLG cells with FTY720, an FDA-approved immunosuppressant drug, counteracts aSyn-induced BDNF downregulation in the cells. We then studied an FTY720 analogue, FTY720-Mitoxy, created by Drs. Perez and Arterburn. We found that FTY720-Mitoxy is not immunosuppressive. Moreover, FTY720-Mitoxy increased expression of BDNF and glial-cell line derived neurotrophic factor (GDNF) in OLG cells, trophic factors that are both downregulated in MSA brains. Furthermore, FTY720-Mitoxy increase GDNF expression in a transgenic mouse model of MSA while also reversing motor dysfunction. Thus, both FTY720 and FTY720-Mitoxy represent promising therapeutic options for patients with MSA. A potential advantage of FTY720-Mitoxy is its ability to increase GDNF expression without causing immunosuppression.