How can oxidative stress contribute to alpha-synuclein pathology/toxicity? What oxidative modifications of alpha-synuclein are relevant to the PD pathogenic process?

Both pathological observations and genetic studies implicate alpha-synuclein as having a central role in the genesis and progression of PD. Alpha-synuclein, however, is expressed by a wide range of neurons and functional areas, but it is the dopaminergic neurons that degenerate during PD (at least initially) and harbour the classical pathological hallmark: the Lewy body. Critically this disease occurs on a background of ageing and also, importantly, a background of differential vulnerability. The effects of oxidative stress are one mechanism which may account for the highly selective vulnerability that occurs in PD.

Oxidative stress is a deleterious condition that results from insufficient scavenging of reactive oxygen species. It has been implicated as a contributing factor in a range of neurodegenerative disorders, although it is not clear whether it is a primary pathogenic event, or an effect of the disease process. Oxidative stress has received special attention in PD research, as a potential pathogenic mechanism primarily because of the capacity for the oxidative metabolism of dopamine to yield hydrogen peroxide and other reactive oxygen species. Critically, these observations may account for the initial vulnerability of the dopaminergic neurons in early stages of PD.  The same cannot be as easily stated for a number of other proposed mechanisms, such as axonal trafficking defects, synaptic dysfunctions etc. which are highly conserved across multiple neuronal subtypes.

The effect of oxidative stress on alpha-synuclein has been widely investigated with variable conclusions. Many studies have assessed the effect of acute oxidative stress to cultured cells, mediated by the addition of hydrogen peroxide, ferric iron, nitrating agents or pesticides.  These studies have described alterations to alpha-synuclein fibril formation and increased aggregation of the protein, as well as changes in its cellular localization, including nuclear accumulation. Oxidative stress is also linked to post-translation modifications of the protein, namely S-nitrosylation, phosphorylation and truncation.  All of these alterations are associated with subsequent changes in the degree and rate of cellular toxicity. However, things are never that simple, and teasing out the individual effect of ROS in these systems, from the likely concomitant ATP inhibition triggered through many of these treatments, is difficult and yet to be resolved experimentally. Interestingly, others have reported an alternate and compelling link between oxidative stress and alpha-synuclein, where chronic exposure - not sufficient to invoke obvious morphological or degenerative changes - leads to an upregulation in endogenous alpha-synuclein. This up-regulation, somewhat counter intuitively, correlates with increased health and less likelihood to undergo subsequent apoptosis in both cortical and dopaminergic neurons. Significantly, this response is not specific to oxidative stress and can be driven by others stressors, suggesting that perhaps alpha-synuclein has a concentration-dependant capacity to be both toxic and protective.  Exposure paradigm, cell type and cell age remain critically important in potentially explaining these conflicting data.

Controversies remain:

• Although attractive in explaining the differential vulnerability that initially characterizes PD - how do we use an oxidative stress driven mechanism to account for the subsequent appearance of Lewy bodies in non-dopaminergic neurons in PD and also for the presence of the same pathological hallmark in the cortex of Dementia with Lewy Bodies? Could this mechanism be a cause in one cell type, and a bystander effect in another?

• It is unlikely that a protein such as alpha-synuclein, that is expressed so broadly and at such high amounts would be without benefit. Subtle differences in expression level appear to have dramatic and perhaps opposing effects on whole cell health after exposure to oxidative stress. Elucidation of the normal function of this protein is therefore critical.

Elevated cytosolic DA levels have been shown to result in increased neurotoxicity in cellular models of PD (Mosharov et al., 2009). In a new study published in the Journal of Neuroscience Research, Gomez-Santos and colleagues confirm these findings in PC12 cells.  They show that extracellular application of DA leads to a dose-dependent decrease in cell viability and to an increase in alpha-synuclein expression mediated at least in part by activation of p38.  They also show that exposure to DA increases the number of autophagic vacuoles and that treatment with 3-MA, an autophagy inhibitor, was protective against DA-mediate cell death. Treatment with nomifensine, a DAT inhibitor, and with antioxidants was also protective.  It would be interesting to test whether treatment with nomifensine and antioxidants prevents the increase in alpha-synuclein expression and to examine by what mechanism p38 and autophagy inhibition result in a decrease in alpha-synuclein expression as reported in this study.