Oxidative stress in neurodegeneration

Abstract

It has been demonstrated that oxidative stress has a ubiquitous role in neurodegenerative diseases. Major source of oxidative stress due to reactive oxygen species (ROS) is related to mitochondria as an endogenous source. Although there is ample evidence from tissues of patients with neurodegenerative disorders of morphological, biochemical, and molecular abnormalities in mitochondria, it is still not very clear whether the oxidative stress itself contributes to the onset of neurodegeneration or it is part of the neurodegenerative process as secondary manifestation. This paper begins with an overview of how oxidative stress occurs, discussing various oxidants and antioxidants, and role of oxidative stress in diseases in general. It highlights the role of oxidative stress in neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. The last part of the paper describes the role of oxidative stress causing deregulation of cyclin-dependent kinase 5 (Cdk5) hyperactivity associated with neurodegeneration.

Figure 1

Summary of role of Cdk5 in physiology and pathology. Cdk5 is a proline-directed serine/threonine kinase and gets activated by its neuron specific promoter p35. Under normal physiological (normal) conditions, Cdk5/p35 is involved with various roles in neuronal development, cognition and memory, cell adhesion, phosphorylation of cytoskeletal proteins, and synaptic plasticity. When the neurons are stressed due to various insults like oxidative stress, inflammation, mitochondrial dysfunction, or toxicity due to Aβ or glutamate, there is an increase in Ca²⁺ leading to activation of calpain, a protease. Calpain cleaves p35 to p25 deregulating Cdk5 activity as p25 forms a hyperactive and more stable complex with Cdk5. Cdk5/p25 activity causes aberrant phosphorylation of various proteins leading to conformational changes inducing gain of toxic function. Misfolded proteins lead to self-aggregation thereby overwhelming the system by blocking transport and disrupting synaptic activity. This ultimately leads to degeneration of neurons and finally be the cause of various neurodegenerative diseases like AD, ALS, PD, and HD.