Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson's Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice

Parkinson's disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of alpha-synuclein (alpha Syn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in alpha Syn pathology in PD brains and is a permissive factor for alpha Syn aggregation. Moreover, we reported that the gene silencing of Syn III in a human alpha Syn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble alpha Syn deposits and dopaminergic striatal synaptic dysfunction, could reduce alpha Syn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human alpha Syn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and alpha-helical alpha Syn. These findings support that the pathological alpha Syn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological alpha Syn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating alpha Syn/Syn III interaction and having the ability to reduce alpha Syn aggregation in vitro and to restore the motility of alpha Syn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of alpha Syn clearing agents for PD therapy.