ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease, for which there is no treatment. Amyotrophic refers to the lack (A-) of muscle (-myo-) nourishment (-trophic), resulting in the wasting of bers, lateral refers to the lateral corticospinal tract of affected neurons between the brain and the spinal cord, and sclerosis is the resultant hardening of the tissue. ALS has also been termed “Charcot’s disease” (maladie de Charcot) after the French clinician Jean Martin Charcot who rst described its pathology in 1869, or in the United States, it is also known as Lou Gehrig’s disease, after the New York Yankees baseball player who was aficted by it. In Europe, it is also known as motor neuron disease, reecting the cells chiey affected, but this term may also refer to a wider group of motor neuron diseases in general. Despite the identication of disorder close to 150 years ago, and a modern understanding of its pathology, ALS remains an ill-dened and fatal disease with few medicinal options and a typical life expectancy of only a few years after diagnosis. New molecular-based understandings of ALS are being elucidated,
Abstract .......................................................................................................................................... 105 8.1 Introduction .......................................................................................................................... 106 8.2 Diagnosis of ALS ................................................................................................................. 106
8.2.1 FALS and SALS ....................................................................................................... 106 8.2.2 Epidemiology of ALS, FALS, and SALS................................................................. 107 8.2.3 Symptoms ................................................................................................................. 107 8.2.4 Pathophysiology ........................................................................................................ 107
8.3 ROS and SOD ....................................................................................................................... 108 8.3.1 Reactive Oxygen Species .......................................................................................... 108 8.3.2 Superoxide Dismutase .............................................................................................. 108
8.4 Cu,ZnSOD (SOD1) ............................................................................................................... 108 8.4.1 Structure ................................................................................................................... 108 8.4.2 Mechanism ................................................................................................................ 109
8.5 ROS in ALS .......................................................................................................................... 110 8.5.1 Dying-Back Hypothesis ............................................................................................ 110 8.5.2 Cu,ZnSOD Mutations and ALS ............................................................................... 110 8.5.3 Cu,ZnSOD and Mitochondria .................................................................................. 111
8.6 Treatment of ALS ................................................................................................................. 112 8.6.1 Pharmacological Interventions ................................................................................. 112 8.6.2 Cu,ZnSOD-Targeting Therapies ............................................................................... 112 8.6.3 Melatonin, Mitochondria, and ALS ......................................................................... 113
8.7 Non-Cu,ZnSOD ALS .......................................................................................................... 113 8.8Conclusions........................................................................................................................... 114 References ...................................................................................................................................... 115
and one important factor is a strong link to reactive oxygen species (ROS) in disease progression. This link between ROS and disease progression includes that mutant products of the SOD1 gene, which encodes a Cu,Zn superoxide dismutase (Cu,ZnSOD) with important functions in removing oxygen free radicals from the cell, can result in ALS. Here, we describe the disease, the links between ROS and ALS, in addition to the current understanding of how Cu,ZnSOD mutations may give rise to the disease pathology.
