Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate

Loss of dopaminergic nigrostriatal neurons and fibrillary alpha-synuclein (alpha-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with alpha-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of alpha-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind alpha-syn and controls alpha-syn-mediated DA overflow and presynaptic compart-mentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and alpha-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied alpha-syn/Syn III co-deposition and longitudinal changes of alpha-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1 - 120) alpha-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOIalisd alpha-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (dthreo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of alpha-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate alpha-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the alpha-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing alpha-syn/Syn III co-aggregates. MPH enhanced full length (fl) alpha-syn/Syn III and even more (1-120) alpha-syn/Syn III interaction in cells exhibiting alpha-syn/Syn M inclusions. Moreover, in silico studies confirmed that MPH may reduce alpha-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of alpha-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management.