Ermanno Valoti, Italy
University of Milano Drug ScienceAuthor Of 1 Presentation
ADVANCEMENT OF SYNAPSIN III AS A THERAPEUTIC TARGET FOR PARKINSON’S DISEASE
Abstract
Aims
Parkinson’s disease (PD) is characterized by a progressive loss of nigral dopamine neurons and deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB). We recently described that synapsin III (Syn III), a synaptic phosphoprotein regulating dopamine release in cooperation with α-synuclein, composes LB insoluble fibrils in PD patients brains, where a marked α-synuclein/Syn III neuropathology was detectable by the in situ proximity ligation assay. We thus investigated whether Syn III might constitute a novel therapeutic target for PD by studying its involvement in α-synuclein aggregation and in the associated nigrostriatal synaptic damage/degeneration and motor symptom onset.
Methods
Different PD in vivo models were used and gene silencing as well as drug-mediated Syn III manipulation were exploited.
Results
We found that Syn III ko mice did not develop fibrillary insoluble α-synuclein aggregates and that their nigrostriatal neurons were protected from both synaptic alterations and degeneration resulting from adeno-associated vector-mediated α-synuclein overexpression. Moreover, gene silencing of Syn III in a human α-synuclein transgenic mouse model at pathological stage could revert α-synuclein aggregation, synaptic derangement and motor symptom onset. Finally, we observed that the monoamine inhibitor methylphenidate, owning Syn III-binding ability, induced a Syn III-reliant motor response in the human α-synuclein transgenic mice independently of its dopamine transporter inhibitory action.
Conclusions
This observation provide a rationale for the freezing of gait-counteracting activity of methylphenidate in advanced PD. Our findings indicate that Syn III is as an accessory mediator of α-synuclein aggregation and toxicity as well as a druggable therapeutic target for PD.