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Reactive Oxygen and Nitrogen Species – A Driving Force in Amyotrophic Lateral Sclerosis

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Systems Biology of Free Radicals and Antioxidants

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating and rapidly progressive neurodegenerative disease. Multiple pathogenic mechanisms contribute to motoneuron injury in ALS that involve the following: (1) misfolded proteins; (2) mitochondrial dysfunction; (3) neurofilament/cytoskeletal alterations; (4) mRNA mishandling from mRNA processing to translation; (5) endoplasmic reticulum (ER) and Golgi dysfunction including ER stress, the unfolded protein response (UPR), and protein degradation malfunction; (6) neuroinflammation with subsequent oxidative injury and neurotoxicity; and (7) astroglial alterations. However, the initiating pathogenic mechanism and the ensuing pathogenic processes responsible for spreading the disease from the original site of initiation are not clearly delineated. Reactive oxygen and nitrogen species (RONS) play significant roles exacerbating disease in ALS by aggravating all of the pathogenic mechanisms that induce motoneuron injury. The reactive species include nitric oxide (NO), superoxide (O2 •−), hydrogen peroxide (H2O2), and peroxynitrite. One of, if not the main source of RONS in the CNS in ALS, is microglia. Microglia are activated at the onset of disease and become increasingly activated with disease progression, generating escalating levels of O2 •− from NADPH oxidase and NO by iNOS. Excess O2 •− is also generated in motoneurons from mitochondrial respiration, and NO is generated by motoneurons and astroglia with disease progression. The NO rapidly reacts with O2 •− to form peroxynitrite, a highly toxic RONS which modifies DNA, proteins, and lipids. In this chapter, the proposed mechanisms of motoneuron injury will each be discussed based on what occurs in patients and animal models, including a discussion on the roles RONS play in aggravating the pathologies.

((it should be just cited at the end unter Acknowledgment was ist done on pa. 3153)

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Acknowledgments

This chapter is published in loving memory of Dr. Jenny S. Henkel who died suddenly and unexpectedly on January 5, 2013. The memory of Dr. Henkel will last through her writings and through the people she touched. May this chapter serve as another wonderful aspect in her brilliant and lasting legacy. She is greatly missed.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Houston, TX, 77030, USA

    Jenny S. Henkel

  2. Department of Neurology, Methodist Neurological Institute, Research Institute, The Methodist Hospital, 6565 Fannin Street Suite, B5-016, Houston, TX, 77030, USA

    David R. Beers, Weihua Zhao & Stanley H. Appel

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  1. Jenny S. Henkel
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  2. David R. Beers
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  3. Weihua Zhao
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  4. Stanley H. Appel
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Correspondence to David R. Beers .

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  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

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Henkel, J.S., Beers, D.R., Zhao, W., Appel, S.H. (2014). Reactive Oxygen and Nitrogen Species – A Driving Force in Amyotrophic Lateral Sclerosis. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_131

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