See Amyotrophic lateral sclerosis

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

Amyotrophic lateral sclerosis (ALS) is a progressive, usually fatal, neurodegenerative disease caused by the degeneration of motor neurons in the central nervous system. No cure has yet been found for ALS. The U.S. Food and Drug Administration (FDA) has approved riluzole as the first drug treatment for the disease. It delays the onset of ventilator-dependence or tracheostomy in selected patients. A Cochrane review states a 9% gain in the probability of surviving one year (see Miller et ah, 2007). 

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O Regan JP, Deng HX, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are assod-ated with farmlial amyotrophic lateral sclerosis [published erratum appears in Nature 1993 Jul 22 364(6435) 362] [see comments]. Nature 362 59-62... 

The discussion here is limited to CuZnSOD for a number of reasons. First, in this system the ping-pong mechanism described in reactions (22) and (23) is operative as written whereas both MnSOD and FeSOD carry out catalysis by mechanisms that involve observable enzyme-substrate complexes under certain conditions. Secondly, this enzymatic system has been studied as a model to look at such factors as electrostatic guidance of substrate (see below). Finally, the link that was demonstrated between over 100 point mutations in CuZnSOD and the inherited version of amyotrophic lateral sclerosis (Lou Gehrig s Disease) has made underscored the importance in understanding details of enzyme function. ... 

A key feature of CuZnSOD is the maintenance of high dismutase activity while shielding the active site copper from other redox transformations [55]. However, it has been repeatedly suggested that apart from its main activity, CuZnSOD shows other enzymatic activities. One reason for these suggestions involved the role of CuZnSOD mutations in the pathogenesis of amyotrophic lateral sclerosis (see Sect. 1.9). 

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