Amyotrophic Lateral Sclerosis ALS

also known as motor neuron disease (MND) and Lou Gehrig s disease, is the most common of a group of disorders in which neurons in the spinal cord and brain stem deteriorate and die, resulting in weakness and muscle deterioration. 

Some studies have associated ALS associated with exposures to solvents,I44-45 60 Hz magnetic fields, and welding,I46l whereas others have questioned these associations. I47 49l A study of twins, however, strongly suggested an association between exposures to solvent chemicals and ALS.1501 As of this writing, the connection between neurotoxic chemical exposure and ALS remains suggestive, but not definitively proven. 

FIGURE 21.11 Different ALS-associated mutations of SODl can increase aggregation of the SODl polypeptide for fundamentally distinct reasons. (From Shaw Valentine, 2007. Copyright 2007 with permission from Elsevier.) 

Amyotrophic lateral sclerosis is an inexorably progressive motor neuron disease, in which both the upper motor neurons and the lower motor neurons degenerate leading to muscle atrophy. Patients eventually experience respiratory failure, usually within three to five years from diagnosis. However, the onset of ALS may be subtle and early symptoms are frequently overlooked. As many as 20,(X)0 Americans have ALS, and an estimated 5,0(X) people in the United States are diagnosed with the disease each year. Onset is usually in the 5th through 7th decade of life. 

ApoE ApolipoproteinE isoforms are the most thoroughly studied ALS candidates. Like AD and PD, ApoE4 appears to have a role in ALS. However, findings for risk and age-at-onset have been inconsistent. The most promising and well supported role for the ApoE4 isoform has been to accelerate disease progression (Al-Chalabi et al., 1996 Moulard et al., 1996). 

NGF Neurotrophic growth factors (NGFs) are a group of neuropeptides that play an important role in regulating the growth, differentiation, and survival of neurons in the peripheral and central nervous systems and are therefore reasonable 

NF Abnormal accumulation of intermediate filaments in the perikarya and proximal axons of motor neurons is a common pathological hallmark of ALS. Several smdies have examined the neurofilament (NF) subunits and repeating regions, but results are mixed with opposite alleles associated with risk in different studies (Figlewicz et al., 1994 Tomkins et al., 1998 Al Chalabi et al., 1999 Skvortsova et al., 2004). 

Free Radicals Oxidative stress appears to play a role in ALS pathogenesis, and studies of genes in the reactive oxidative pathways and reactive nitrogen pathways are ongoing. 

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Amyloid Precursor Protein Amyotrophic Lateral Sclerosis (ALS)... 

Interest in superoxide dismutase has increased in recent years with the discovery that a mutation in the gene coding for SOD is linked to certain types of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig s disease. Exactly how mutant forms of SOD are involved in ALS is a subject of intense research. 

Lou Gehrig s disease (amyotrophic lateral sclerosis ALS) displays motor neuron deposits of hyperphosphorylated neurofilament subunits in the sporadic disease. Familial ALS, some 20% of all cases of ALS, involves dominant superoxide dismutase SOD1 mutants that can form (3-barrel aggregates [49-51]. 

Ciliary neurotrophic factor (CNTF) decreases naturally occurring and axotomy-induced cell death and has been evaluated as a treatment for neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS)... 

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... 

The motor neuron diseases (MND), including amyotrophic lateral sclerosis (ALS), are chronic, progressive illnesses characterized by severely disabling clinical features... 

Bruijn, L. I., Beal, M. F., Becher, M. W. et al. Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. Proc. Natl Acad. Sci. U.S.A. 94 7606-7611,1997. 

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurones. In 15-25% of cases, the genetic cause of the disease is a mutation of the enzyme Cu+/Zn2+... 

Frontotemporal dementia involves an early and primary degenerative process of frontal and/or temporal cortex. Several disorders fall under this rubric, such as Pick s disease and the dementia associated with amyotrophic lateral sclerosis (ALS). ALS is a degenerative disease of upper motor neurons that is sometimes accompanied by a frontal lobe dementia (Vercelletto et al. 1999 Abe et al. 1997). ALS has been associated with mutations in the free radical scavenging enzyme superoxide dismutase 1 (Price et al. 1997). Pick s disease is associated histologically with a loss of neurons and cytoplasmic Pick bodies in surviving neurons. 

In this section, we will more particularly detail two neurodegenerative diseases for which GBP loss of function has clearly been reported by several studies and in which a therapeutic strategy based on resetting acetylation levels has been tested in vivo Polyglutamine disorders and Amyotrophic lateral sclerosis (ALS). 

Amyotrophic lateral sclerosis (ALS) is a disease of the neurons that control muscle movement (motor neurons). Degeneration of neurons causes muscle atrophy eventually impairing the movement of people afflicted with the disease. 

It shows significant activity against a spectmm of neurodegenerative disorders in animal models that replicate many of the features of important human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson s disease [147]. 

Amyotrophic lateral sclerosis (ALS), peroxyni-trite implicated, 46 402 Anabaena, heterocyst ferredoxin, 38 229 Anabaena sphaeria, ferredoxins, 38 228-229 Anaerobic controlled potential electrolysis, Azotobacter, 38 129... 

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). 

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