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The alpha-synuclein protein is targeted by the proteasome (Bennett et al.1999) but we do not yet know if it is the mutations that affect its stability and therefore lead to its eventual accumulation and subsequent disruption of the cellular function. This is a vital point that we shall return to later. Although we can demonstrate that the Lewy bodies contain alpha-synuclein and varying amounts of ubiquitin, the experimental evidence does not show whether it is conjugated synuclein that forms the major part of the accumulated material.

There is new evidence that experimental accelerated formation of inclusion bodies by the mechanism of proteasome inhibition, actually protects against dopaminergic cell death which is actually contrary to previous experimental prediction (Setsuie et al 2005). This implies that the relationship between ubiquitin-proteasome system and dopaminergic cell death is clearly more complex than was originally thought.

There is a German family that has been extensively investigated, who carry a variant mutation of the UCH-L1coding gene which manifests itself as Parkinson's disease (Leroy et al. 1998). It would appear that this mutation does not completely impair the function of the enzyme, but reduces its ability to function. From evidence gleaned from the study of this family it would appear that this mutation results in a reduction of the amount of free ubiquitin inside the cells and, as a result, there is less ubiquitin available to degrade other (as yet unidentified ) toxic proteins. It is worthy of note that a mutation in this same gene, UCH-L1, is responsible for another neuro-degenerative disease called gracile axonal dystrophy in mice which has the clinical manifestation of sensory ataxia followed by motor ataxia as the disease progresses. (Saigoh et al. 1999)
Another important protein which is relevant to the pathology of Parkinson's disease is known as Parkin, which is a 465 amino acid residue protein which has certain structural and topographical similarities to ubiquitin at the NH end and a RING finger structure at the -COOH end. Mutations in the same gene appear to produce the Autosomal-recessive Juvenile Parkinson's variant which is the commonest familial form of Parkinson's disease (Kitada et al. 1998). This variant does not have the Lewy bodies which are the trade mark of the sporadic forms of the disease.

Parkin has been identified as a ubiquitin-protein ligase (Shimura et al 2000) which appears to act in conjunction with enzymes UBCH7 and UBCH8. Investigations have shown that the mutant Parkin from patients with Autosomal-recessive Juvenile Parkinson's variant have lost the ubiquitin ligase activity (Zhang et al. 2000).