Loss of dopaminergic nigrostriatal neurons and fibrillary a-synuclein (a-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 a-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of a-syn aggregation and toxicity.Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind a-syn and controls a-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and a-syn polymorphisms and constituting a risk factor for the development of LB disorders.Here, we studied a-syn/Syn III co-deposition and longitudinal changes of a-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) a-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6¿J wild type (wt) and C57BL/6JOlaHsd a-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of a-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate a-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the a-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 a-syn/Syn III co-aggregates. MPH enhanced full length (fl) a-syn/Syn III and even more (1–120) a-syn/Syn III interaction in cells exhibiting a-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce a-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 a-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management.

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