Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases belong to the so-called "protein conformational diseases" and affect several thousands of aged people all over the world. Cells have evolved mechanisms such as the unfolded protein response, where chaperons can rescue misfolded proteins by breaking up aggregates and assisting the refolding process, while proteins that cannot be rescued by refolding are delivered to the proteasome by other chaperones to be recycled. In general, protein conformational diseases are conditions that arise from the dysfunctional aggregation of proteins in non-native conformations. This is often associated with multiple metabolic derangements that result in the excessive production of reactive oxygen species (ROS) and oxidative stress. These ROS set in motion a host of redox reactions which can result in unstable nitrogen and thiol species that contribute to additional redox stress (1,2).

Nitric oxide (NO) is a gaseous modulator produced by the NO synthase (NOS) family and it is involved in several cellular functions, such as neurotransmission, the regulation of vessel tone and immune response. Unfortunately, if NO is produced in excess or if the cell is in a pro-oxidant redox, NO undergoes oxidative/reductive reactions producing toxic compounds and promoting cell damage (3,4). Recently the term "nitrosative stress" has been used to indicate the cellular damage elicited by NO and its congeners peroxyni-trite (OONO-), N2O3, nitroxyl anion and nitrosonium (all can be indicated as reactive nitrogen species (RNS)) (5-7). Nitrosative stress has been implicated in the pathogenesis of neurodegenerative disorders (4). The first studies led to the hypothesis that RNS, such as peroxynitrite formed after the reaction of NO with superoxide anion, was responsible for the cellular damage in neurodegenerative disorders; this view put in a common frame either oxidative stress or nitrosative stress and it is still the current hypothesis to explain the contribution of nitrosative stress in AD (3,4). More recently, it has been proposed that NO itself can trigger neurodegeneration through a direct interaction with thiol groups of specific proteins such as matrix metalloproteinases (MMPs) or parkin, thus raising a new scenario in the pathogenesis of PD (8-10).

The ability of a cell to deal with ROS and RNS requires the activation of pro-survival pathways as well as the production of molecules endowed with antioxidant and

Oxidative Stress and Neurodegenerative Disorders Edited by G. Ali Qureshi and S. Hassan Parvez

© 2007 Elsevier B.V. All rights reserved.

anti-apoptotic activities. Among the cellular pathways involved in the protection against oxidative and nitrosative stresses, the heat shock protein (Hsp) family plays a key role, in particular in brain cells. Hsp70, Hsp60, Hsp27 and ubiquitin are the functional chaperones triggering a cascade of intracellular events, which are collectively known as the unfolded cell stress response. Heme oxygenase-1 (HO-1), also referred to as Hsp32, belongs to the Hsp family and protects brain cells from oxidative stress by degrading toxic heme into free iron, carbon monoxide (CO) and biliverdin (BV). Biliverdin is then reduced by biliverdin reductase (BVR) into bilirubin (BR), a linear tetrapyrrole with antioxidant properties (3,11-14). Very recently, BR has been shown to effectively counteract nitrosative stress also, due to its ability to bind and inactivate NO and RNS (15-17).

In this chapter, the importance of nitrosative stress in the pathogenesis of brain aging and neurodegenerative disorders as well as the key role played by HO-1 in modulating the onset and progression of AD and PD are discussed.

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