**6. Conclusions**

152 Etiology and Pathophysiology of Parkinson's Disease

Noteworthy, despite their different localization in subregions of the adult brain (Pieribone et al., 2002;Cesca et al., 2010) synapsin 1 and 3 share a strong structural homology in their functional domains (Hosaka and Sudhof, 1998), suggesting that they may likely interact with similar proteins and cytoskeletal components, although they differentially regulate

neurotransmitter release (Kile et al., 2010;Feng et al., 2002;Cesca et al., 2010).

Fig. 2. Schematic representation of the physiological and pathological localization of αsynuclein within dopaminergic synapses. Alpha-synuclein aggregation may compromise dopaminergic synaptic release by altering the subcellular localization of key proteins

Thus, it is likely that α-synuclein can also interact with- and modulate synapsin 3. As a support to this notion, previous reports have shown that synapsin 1 levels in the striatum of PD patients are comparable to those of control subjects (Girault et al., 1989), thus suggesting that synapsin 1 is not specifically implicated in the pathophysiology of nigrostriatal dopamine deficiency in PD. Thus, α-synuclein and synapsin 3 likely share common regulatory roles in nigrostriatal dopaminergic synapses suggesting that α-synuclein accumulation may critically affect the function of synapsin 3 by altering its levels and distribution. In particular, an increase and redistribution of α-synuclein and synapsin 3 complexes in striatal dopaminergic synapses could be associated to deregulation or loss of dopamine release as both proteins are negative regulators of this event. Furthermore,

involved in this process.

A large body of evidence strikingly indicate that α-synuclein pathology at the synapse may be crucially involved in PD pathophysiology. Indeed, α-synuclein accumulation, pathological modifications and aggregation are able to significantly impair synaptic functions in experimental models of PD. In particular, it appears that α-synuclein aggregation at dopaminergic synaptic sites may damage neuronal functions by affecting the correct subcellular distribution of several molecular members of its lipidome and proteome, thus leading to synaptic vesicle stall and to the consequent block of synaptic release. This event may underlie the onset of a perilous axonal degeneration which may retrogradely compromise neuronal resilience, thus leading to dopaminergic cell dysfunctions and death. This view opens the way to the discovery and characterization of novel possible targets to develop drug- and gene-based therapeutical strategies to cure the disease, possibly by modifying and/or slowing disease progression. This is a crucial point, as current therapeutical approaches for PD are aimed at ameliorating disease simptomathology, but none of the present known agent is able to block the progression of the disease. Targeting the α-synuclein-related synaptic proteome by drug-based or gene-based therapeutical interventions may thus represent a new frontier to develop disease modifying strategies for PD and other α-synucleinopathies.
