Abstract
Parkinson’s disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron’s autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson’s disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson’s disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson’s disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson’s disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic.
Highlights
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS), are commonly associated with both protein aggregation and oxidative stress.The protein deposits are clearly visible and have attracted considerable attention
Candidate toxins have been elusive, we recently described hypochlorite-oxidized cysteinyl-dopamine (HOCD), a cytotoxin formed by exposing cysteinyl-dopamine to hypochlorite [4]
HOCD along with α-synuclein aggregation may contribute to an excessive and unsustainable demand for autophagy, triggering regulated cell death. To put this in a broader context, we will begin with brief discussions of autophagy/proteinopathy and mitophagy/oxidative stress and consider how HOCD may contribute to the selective death of dopaminergic neurons
Summary
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS), are commonly associated with both protein aggregation and oxidative stress. A further implication is that autophagy overload may be caused by either excessive protein aggregation or extreme oxidative stress. In the context of Parkinson’s disease (PD), the unique vulnerability of dopamine neurons to oxidative stress has received considerable attention. HOCD along with α-synuclein aggregation may contribute to an excessive and unsustainable demand for autophagy, triggering regulated cell death. To put this in a broader context, we will begin with brief discussions of autophagy/proteinopathy and mitophagy/oxidative stress and consider how HOCD may contribute to the selective death of dopaminergic neurons
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