Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells

α-synuclein is a chaperone-like protein implicated in Parkinson's disease (PD). Among α-synuclein's normal functions is an ability to bind to and stimulate the activity of the protein Phosphatase 2A (PP2A) catalytic subunit in vitro and in vivo. PP2A activity is impaired in PD and in dementia with Lewy Bodies in brain regions harboring α-synuclein aggregates. Using PP2A as the readout, we measured PP2A activity in response to α-synuclein, ceramides, and FTY720, and then on the basis of those results, we created new FTY720 compounds. We then measured the effects of those compounds in dopaminergic cells. In addition to stimulating PP2A, all three compounds stimulated the expression of brain derived neurotrophic factor and protected MN9D cells against tumor-necrosis-factor-α-associated cell death. FTY720-C2 appears to be more potent while FTY720-Mitoxy targets mitochondria. Importantly, FTY720 is already FDA approved for treating multiple sclerosis and is used clinically worldwide. Our findings suggest that FTY720 and our new FTY720-based compounds have considerable potential for treating synucleinopathies such as PD.

BDNF; PP2A; Parkinson’s; ceramides; synucleinopathy; triphenylphosphonium; α-Synuclein.