Abstract
While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis.
Highlights
One possible unifying molecular mechanism that can induce both the formation of protein inclusions and neuron degeneration is the oxidative reactions derived from the production of reactive oxygen and nitrogen species
These observations do not demonstrate that oxidative processes are the sole cause of neuronal demise, they are consistent with data in animal and cellular model systems that establish a role for oxidation in neurodegeneration and death
We propose that the combined interactions of these three interrelated molecular pathways – oxidative modifications, mitochondrial dysfunction, and impaired protein degradation – constitute a "Bermuda Triangle" that induces neuron death
Summary
Examining the "Bermuda triangle" in which dopamine neurons are lost, oxidative modifications, mitochondrial dysfunction, and impaired protein degradation appear to be three interrelated molecular pathways responsible for the pathogenesis of both sporadic and familial PD (Figure 1). Evidence from environmental, genetic, and endogenous factors highlights the interplay of these three mechanisms as the common detrimental denominators inducing neuronal death Do these three processes have clear impacts on cellular viability, but their participation explains other characteristic features of disease, such as the presence of oxidized proteins, inclusions, increased prevalence with late age, and dopaminergic regional selectivity. Together, through their effects on cellular homeostasis and their interactions with one another, oxidative stress, mitochondrial dysfunction, and impaired protein degradation provide the final impetus with which insult to neurons is transformed into neurodegenerative disease. PD: Parkinson's Disease; UPS: Ubiquitin Proteasome System; CMA: Chaperone Mediated Autophagy; MPTP: 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA: 6Hydroxy Dopamine; PINK1: PTEN-Induced Kinase 1; LRRK2: Leucine-Rich Repeat Kinase 2; SOD: Superoxide dismutase; NOS: Nitric oxide synthase
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