Metal catalyzed oxidation of alpha-synuclein--a role for oligomerization in pathology?

A number of studies have demonstrated a role for transition metals and oxidative stress in the etiology of Parkinson's disease (PD). Genetic and biochemical evidence also clearly links the protein alpha-synuclein (alphaSyn) to PD and a number of associated diseases. In these "synucleinopathies", alphaSyn is deposited, often in oligomerized forms, as cytoplasmic inclusions known as Lewy bodies and Lewy neurites. alphaSyn cross-linking/oligomerization can occur via a number of processes, most stimulated by metal catalyzed oxidation (MCO). In PD, the increased sensitivity of midbrain neurons expressing high levels of oxidizable catecholamines may provide one clue to account for degeneration of these neurons. In other regions of the nervous system that develop Lewy body pathology, the mode of alphaSyn oligomerization is less clear. Thus, the relationship between alphaSyn and MCO, either direct or indirect, represents a particular concern for possible treatment of these various diseases.