Als Is A Disease Of Motor Neurons

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ALS is a fatal neurological disease that causes a movement disorder (Table III) characterized by progressive muscle weakness, muscle atrophy, and eventual paralysis. Individuals affected with ALS die within 3-5 years of clinical onset. This disease is neuropathologically characterized by progressive degeneration of the upper and lower motor neurons in the brain and spinal cord (Table I, Fig. 6). The neuropathology of ALS is primary degeneration of the upper (motor cortical) and lower (brain stem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in the spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Two major forms of ALS exist: idiopathic (sporadic) and heritable (familial). The vast majority of ALS cases are sporadic with no known genetic component. The familial forms of ALS (FALS) are autosomal dominant and make up about 10-20% of all ALS cases. In a subset of familial ALS cases (about 5-10%), missense mutations have been identified in the gene for superoxide dismutase 1 (SOD1), also called copper-zinc superoxide dismutase (Table II).

A variety of theories have been proposed for the possible causes of neurodegeneration in ALS (Table VI). A major center of attention is the mutant forms of SOD1 found in FALS. Because SOD1 is widely expressed in cells throughout the body and in CNS tissue the expression is very ubiquitous, the basis for the selective vulnerability of motor neurons in the presence of SOD1 mutations is still not clear. Initial experiments hinted that mutations in SOD1 could lead to motor neuron degeneration by decreasing enzy matic activity, resulting in neurotoxicity of reactive oxygen species, notably superoxide radicals that are inefficiently scavenged by mutant SOD1. However, it was found that FALS-linked mutations in SOD1 generally do not impair enzymatic activity but instead decrease protein stability. It was then proposed that mutant SOD1 acquires a neurotoxic gain in function. Mutations in SOD1 may convert this enzyme from a protein with antioxidant-antiapoptotic functions to a protein with apoptosis-promoting effects. In addition to the dismutation of superoxide, SOD1 also has peroxidase activity, and this peroxidase activity is enhanced in mutant SOD1 compared to normal SOD1. This gain of function could lead to the enhanced production of reactive oxygen species that could damage motor neurons. In mice with forced expression of mutant forms of the gene encoding for SOD1, motor neuron degeneration does occur. Unfortunately, however, this degeneration in transgenic mice overexpressing mutant forms of SOD1 is neuro-pathologically different from the degeneration of motor neurons in people with sporadic and familial ALS.

Studies have identified that the degeneration of motor neurons in ALS is a form ofapoptotic cell death that appears to occur by a programmed cell death (PCD) mechanism (Fig. 7). PCD is a type of cell death that is triggered by intrinsic cellular pathways involving specific death proteins. This PCD of motor neurons in ALS could be due to a gain in function of the tumor suppressor protein p53. p53 is a DNA-binding phosphoprotein that functions in genome surveillance, DNA repair, and gene transcription. p53 commits to death cells that have sustained DNA damage from genotoxic agents and reactive oxygen species. DNA lesions have been found in individuals with ALS possibly because of free radical damage and defective DNA repair. Thus, p53 may participate in the mechanisms for motor neuron death in ALS in response to DNA damage. The gene expression of some cell death proteins is promoted by p53. For example, the levels of a protein called Bax (see Table IV) are regulated by p53. Bax is critical for neuronal

Table III

Classification of Some Movement Disorders in Humans

Motor neuron diseases Akinetic disorders Hyperkinetic disorders Ataxic disorders

Amyotrophic lateral sclerosis Parkinson's disease Huntington's disease Spinocerebellar degeneration

Spinal muscular atrophy Progressive supranuclear palsy Dystonia Ataxia-telangiectasia

Figure 6 Motor neurons degenerate in patients with ALS. (A) In normal control individuals, the anterior horn of the spinal cord (brackets) is populated with many neurons (black dots within brackets). Scale bar = 0.7mm (same for B). (B) In ALS, the anterior horn is depleted of neurons (brackets). (C) The anterior horn of the spinal cord in normal subjects is populated with large, multipolar motor neurons (arrows). Scale bar = 200 mm (same for D). (D) In ALS, the anterior horn contains many shrunken neurons (arrows) instead of large multipolar cells.

Figure 6 Motor neurons degenerate in patients with ALS. (A) In normal control individuals, the anterior horn of the spinal cord (brackets) is populated with many neurons (black dots within brackets). Scale bar = 0.7mm (same for B). (B) In ALS, the anterior horn is depleted of neurons (brackets). (C) The anterior horn of the spinal cord in normal subjects is populated with large, multipolar motor neurons (arrows). Scale bar = 200 mm (same for D). (D) In ALS, the anterior horn contains many shrunken neurons (arrows) instead of large multipolar cells.

apoptosis. In ALS, we have found that p53 levels are elevated and that this p53 has competent DNA binding activity; moreover, Bax levels are elevated in individuals with ALS. This information is novel and is conceptually very important for further understanding the pathobiology of motor neuron death in ALS. It suggests that critical molecular mechanisms for regulating human cancer are overactive in vulnerable CNS regions in a human-age-related neurode-generative disease. This theory may advance the

Table IV

Leading Theories on the Possible Causes of Motor Neuron Degeneration in ALS

Mechanism

Comment

SOD1 mutation Excitotoxicity Neurotrophin withdrawal DNA damage-repair defects Autoimmunity

Aberrantly occurring programmed cell death

Found in some FALS cases. Resulting in a toxic gain in function or modified stability of SOD1.

Resulting from abnormal glutamate receptor activation and defects in glutamate transport.

Resulting from insufficient muscle cell- or glial-cell-derived trophic support or defective neurotrophin receptor signaling.

Resulting from oxidative stress or inefficient DNA repair enzyme function. May involve both mitochondrial and nuclear DNA damage.

Resulting from autoantibodies to motor neuron antigens.

May be triggered by all of the precedings mechanisms.

Figure 7 Motor neuron degeneration in ALS is a form of apoptosis that may be mediated by a p53-dependent mechanism. (A) Normal appearing spinal motor neuron with a large, multipolar cell body and a large nucleus (asterisk) containing a reticular network of chromatin and a large nucleolus. Scale bar = 7 mm (same for B). (B) Near end stage apoptotic motor neuron in ALS (arrow). The cell has shrunken to about 10% of normal size and has become highly condensed. (C and D) Nuclear DNA fragmentation (asterisk) occurs in motor neurons in patients with ALS as the nucleus condenses (asterisks) and the cell shrinks. Scale bar = 7 mm. (E) In individuals with ALS, p53 accumulates in the nuclei (asterisk) of motor neurons (arrow). The nearby neuron (open arrow) has an unlabeled nucleus for comparison. Scale bar = 10 mm. (See color insert in Volume 1).

understanding of motor neuron degeneration in ALS and perhaps other age-related neurodegenerative disorders in which chronic and progressive DNA damage may occur.

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