Publication date: Feb 04, 2020
Loss of dopaminergic nigrostriatal neurons and fibrillary ?-synuclein (?-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 ?-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of ?-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind ?-syn and controls ?-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 ?-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied ?-syn/Syn III co-deposition and longitudinal changes of ?-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) ?-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6?J wild type (wt) and C57BL/6JOlaHsd ?-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 ?-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate ?-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the ?-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 ?-syn/Syn III co-aggregates. MPH enhanced full length (fl) ?-syn/Syn III and even more (1-120) ?-syn/Syn III interaction in cells exhibiting ?-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce ?-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 ?-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management.
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Faustini, G., Longhena, F., Bruno, A., Bono, F., Grigoletto, J., La Via, L., Barbon, A., Casiraghi, A., , Straniero, Valoti, E., Costantino, G., Benfenati, F., Missale, C., Pizzi, M., Spillantini, M.G., and Bellucci, A. Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate. 23902. 2020 Neurobiol Dis.