What causes the build-up of ubiquitin-containing inclusions in Parkinson's disease?

Parkinson's disease (PD) is characterized by the presence of neuronal inclusions in the midbrain known as Lewy bodies. These proteinaceous intracellular deposits may contribute to subsequent dopaminergic neurodegeneration in this brain region. While it is assumed by many investigators that immunopositive ubiquitin staining in Parkinson's-associated Lewy bodies represents the presence of elevated levels of intracellular ubiquitin-protein conjugates, this has yet to be definitively proven. Increases in oxidative stress along with decreased levels of the thiol regulatory molecule glutathione in the midbrain in PD may cause S-thiolation of important components of the ubiquitination system drastically reducing their activities and in fact impairing the cell's ability to ubiquitinate proteins at all. Here, we review evidence for free versus protein-bound ubiquitin in Parkinsonian-associated Lewy bodies and discuss future directions towards resolving this important question as well as its implication for future treatment therapies.