 | NITRIC OXIDE: NOVEL ACTIONS, DELETERIOUS EFFECTS, AND CLINICAL POTENTIAL
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 962:182-194 (2002)
© 2002 New York Academy of Sciences
Hypothesis: Proteasomal Dysfunction
A Primary Event in Neurogeneration that Leads to Nitrative and Oxidative Stress and Subsequent Cell Death
BARRY HALLIWELL
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore
Address for correspondence: Barry Halliwell, Department of Biochemistry, Faculty of Medicine, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260. Voice: +65 874 3247; fax: +65 779 1453.
bchbh{at}nus.edu.sg
Ann. N.Y. Acad. Sci. 962: 182-194 (2002).
It is proposed that a primary mechanism leading to neuronal cell death in common neurodegenerative diseases is interference with proteasome function. This can involve genetic defects, direct inactivation of the proteasome (e.g., by reactive oxygen species), or overloading with proteins. The latter can be caused by excessive production of normal proteins or by the formation of poorly degradable proteins as a result of genetic mutations, faulty posttranslational modification, or protein modification by reactive oxygen or nitrogen species. Blockage of the proteasome leads to increased oxidative and nitrative stress, the latter apparently due to upregulation of nitric oxide synthase. Thus, agents that increase proteasome function may be generally neuroprotective, as may be NOS inhibitors. Proteasome inhibitors should be used with caution as therapeutic agents.
Key Words: proteasome • nitric oxide • neurogeneration • oxidative stress • Alzheimer's disease Abbreviations: AD Alzheimer's disease. • ALS Amyotrophic lateral sclerosis. • COX-2 Cyclooxygenase-2. • CuZnSOD Copper, zinc-containing superoxide dismutase. • FA Freidreich's ataxia. • GSH Glutathione, reduced. HNE 4-Hydroxy-trans-nonenal. • MSA Multiple system atrophy. • NOS Nitric oxide synthase. • PD Parkinson's disease. • SOD Superoxide dismutase
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