The Ubiquitin Proteasome System is a multi-enzymatic pathway which degrades polyubiquinated soluble cytoplasmic proteins. This biochemical machinery is impaired both in sporadic and inherited forms of Parkinsonism. In the present paper we focus on the role of the pre-synaptic protein alpha-synuclein in altering the proteasom based on the results emerging from experimental models showing a mechanistic chain of events between altered alpha-synuclein, proteasome impairment and formation of neuronal inclusions and catecholamine cell death.