Synapsin III Alteration in Parkinson's disease

The main neuropathological hallmarks of Parkinson’s disease (PD) are loss of nigro-striatal dopamine neurons and intraneuronal Lewy Bodies (LB), proteinaceous inclusions mainly composed by α-synuclein. Recently, we found that α-synuclein interacts and cooperates with a specific member of the synapsin phosphoprotein family: synapsin III, in the regulation of dopaminergic neuron function. The aim of this study was to investigate whether synapsin III alterations may be related to α-synuclein pathology in PD. We thus investigated the occurrence of alterations of synapsin III expression and distribution in “in vitro” and “in vivo” experimental models and in the post-mortem PD brain (Human brain samples were kindly provided by the UK Parkinson’s disease Brain Bank). In the experimental models of PD, we found that α-synuclein aggregation induced an increase and redistribuition of synapsin III in dopaminergic neurons. Interestingly, by silencing synapsin III “in vitro” we could prevent α-synuclein aggregation and the onset of associated synaptic changes. By immunohistochemistry, we showed a marked accumulation of synapsin III in the caudate/putamen of patients affected by PD when compared to age matched controls. In addition, many LB-like structures in the substantia nigra of PD patients as well as in the hippocampus of a patient affected by DLB were found to be immunoreactive for synapsin III, that by confocal fluorescence microscopy resulted to be accumulated in the core of LB. By co-immunoprecipitation, we found that synapsin III directly interacted with α-synuclein in mice and human brain. Finally, western blot analysis showed significant alterations of synapsin III levels that correlated with alteration of α-synuclein in the caudate/putamen and substantia nigra of PD patients. Altogether, our data support a critical involvement of synapsin III in PD pathophysiology.