Amyotrophic lateral sclerosis, neuronal degeneration

Ac5. Amyotrophic lateral sclerosis a. Degeneration and loss of upper and/or lower motor neurons... 

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 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. 

Accelerated apoptotic cell death has been observed in many neurodegenera-tive diseases such as Alzheimer s disease (K7), Huntington disease (W9), amyotrophic lateral sclerosis (K12), cerebellar degeneration (T4), neuron degeneration in Down s syndrome (B16), Parkinson s disease (J1), and retinitis pigmentosa (R1). 

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). 

There are a myriad of known and suspected mechanisms by which diseases can modify chemical neurotransmission. These can vary from no transmission, as in the case of a degenerated or absent neuron, to too much neurotransmission from a malfunction of the synapse. One of the key consequences of loss of neurons in neuro-degenerative disorders such as Parkinson s disease, Huntington s disease, amyotrophic lateral sclerosis (Lou Gehrig s disease), and Alzheimer s disease, is the fact that no neurotransmission occurs subsequent to neuronal loss (Fig. 4—24). This is a conceptually simple mechanism of disease action with profound consequences. It is also at least in part the mechanism of other disorders, such as stroke, multiple sclerosis, and virtually any disorder in which neurons are irreversibly damaged. 

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. 

The disease models can be grouped into four primary categories (Fig. 20.1). (1) Motor neuron diseases, in which the death of motor neuron somata in the spinal cord results in denervation of the muscles, progressive flaccid paralysis, and usually premature death. In humans, examples of such diseases would include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). (2) Peripheral neuropathies, in which axonal integrity or conduction is not maintained, resulting in axon degeneration and impaired connectivity of the nervous system and the musculature. 

Amyotrophic lateral sclerosis (ALS) In UK, known as motor neuron disease. A devastating adult onset paralytic disorder caused by degeneration of large motor neurons in the brain and spinal cord. 

Amyotrophic lateral sclerosis is an inexorably progressive motor neuron disease, in w hich both the upper motor neurons and the lov er motor neurons degenerate leading to muscle atrophy. Patients eventually experience respiratory failure, usually within three to five years from diagnosis. However, the onset of AES may be subtle and early symptoms are frequendy overlooked. As many as 20,000 Americans have ALS, and an estimated 5,000 people in the United States are diagnosed with the disease each year. Onset is usually in the 5th through 7th decade of life. 

Van Damme P, Braeken D, Callewaert G, Robberecht W, Van Den Bosch L (2005) GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis. J Neuropatli Exp Neurol 64(7) 605-612. 

Pullen AH, Demestre M, Howard RS, Orrell RW (2004) Passive transfer of purified IgG from patients with amyotrophic lateral sclerosis to mice results in degeneration of motor neurons accompanied by Ca2-i- enhancement. Acta Neuropathol (Berl) 107 35 6. 

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