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Amyotrophic lateral sclerosis: Hypothetical pathogenesis
Medical Hypotheses I Medical Hypotheses (1994) 42, 393-394 Q Longman Cimup Ltd 1994
Amyotrophic Lateral Sclerosis: Hypothetical Pathogenesis D. W. BROWN 55 Smyma Powder Springs Road SE, Marietta, GA 30060, USA.
Abstract - A hypothetical pathogenesis for a typical case of amyotrophic lateral sclerosis (ALS) follows from opinions of Rowland and results of neuroscientists at Baylor. ALS might typically result from an autoimmune disorder that causes IgG to enhance release of acetylcholine (ACh) from axon terminals. Motor neuron overactivity associated with fasciculation might result from enhanced release of ACh which is taken up by nicotinic ACh receptors. Increased levels of intracellular calcium ions might result from motor neuron overactivity associated with fasciculation. Neuronal cell degeneration and death might result from increased levels of intracellular calcium ions.
Hypothetical
pathogenesis
Rosen et al (1) demonstrate that familial variants of amyotrophic lateral sclerosis (ALS) are linked to mutations in the gene which encodes cytosolic superoxide dismutase (SODl), an enzyme essential for the elimination of toxic superoxide anions; however, only about 10% of ALS cases are of the familial type. McNamara and Fridovich (2) suggest how the decrease of SOD1 activity might explain the excitotoxic mechanisms of motor neuron death. What might be the pathogenesis of the typical case of nonfamilial ALS? Immunoglobulin (Ig) G from ALS patients can enhance release of acetylcholine (ACh) from axon terminals at the neuromuscular junction (3). Neuronal cell degeneration and death in ALS (as well as ischemia/hypoxia and hypoglycemia) are related to increased levels of intracellular calcium ions (4). Rowland (5) claims that fasciculation is a sign of disorder of the perikaryon and that both fasciculation and fibrillation tend to occur where there is disorder
of the perikaryon and the peripheral nerve; clinical fasciculation is evident in some sensorimotor neuropathies, but everyday clinical experience indicates that fasciculations rarely occur in sensorimotor neuropathies. When neurons fire repeatedly, potassium ions accumulate in the extracellular space; astrocytes, because of their high permeability to potassium ions, can take up and store the excess potassium ions so as to protect the neighboring cells from excessive membrane depolarization (6). If motor neuron overactivity is prolonged, then the astrocytes might fail to adequately buffer the excess potassium ions; in ALS, the proliferation of astrocytes might be correlated with accumulation of potassium ions in the extracellular space. Motor neurons have voltage-gated calcium channels that open in response to membrane depolarization. Researchers originally assumed that in ALS the voltage-gated calcium channels are the channels through which excess calcium ions enter the motor neurons; more recent studies have suggested that in
Date received 7 October 1993 Date accepted 20 December 1993
393
394
MEDICAL HYPOTHESES
ALS a pathogenically important part of the calcium ion influx also occurs via ligand-gated calcium channels (4). As neuronal activity increases, neurons release more potassium ions and receive more calcium ions. Thus, motor neuron overactivity which is associated with fasciculation might cause high levels of intracellular calcium ions. If the presence of fasciculations really does tend to distinguish ALS from peripheral neuropathy (PN), then increased levels of intracellular calcium ions might typically result from two distinct types of motor neuron overactivity in ALS and PN. One type of overactivity would be associated with fasciculation in ALS and with enhanced release of ACh, and another type of overactivity would be associated with fibrillation in PN and with increased activation of voltage-gated calcium channels. If the typical case of ALS results from an autoimmune disorder, then it might be instructive to consider two other autoimmune disorders: myasthenia gravis and Lambert-Eaton syndrome. Myasthenia gravis is typically an autoimmune disorder in which antibodies are produced against the nicotinic ACh receptor; whereas, Lambert-Eaton syndrome is attributed to the presence of antibodies to voltagegated calcium channels in the presynaptic terminal (7). Consider a hypothetical table:
receptors, there might be many exceptions even for nonfamilial ALS cases. Also, enhanced release of ACh might have a variety of causes. Conclusion This communication offers speculation that ALS IgG leads to enhanced release of ACh; the consequent increase in motor neuron activity then causes increased levels of intracellular calcium ions and eventual cell death. If the preceding speculation is true, then ALS might respond favorably to agents which block the nicotinic ACh receptor. Even if the preceding speculation is false, Appel’s view (4) of the role of intracellular calcium ions in neuronal degeneration and of the role of the interaction of ALS IgG with voltagegated calcium channels would imply that autoimmune disorders might account for most cases of nonfamilial ALS. Are immunosuppressive drugs the best therapy for the typical case of ALS? It is conceivable that the thymus contains ACh receptors in a particularly antigenic form (9). Antibodies against nicotinic ACh receptors might cause a primary enhancement of ACh release or a secondary proliferation of ACh receptors. Is thymectomy an effective therapy for ALS in a significant percentage of cases? References
Nicotinic ACh
receptors Blockade Proliferation
Voltage-gated calcium channels
myasthenia gravis Lambert-Eatonsyndrome one form of ALS one form of PN
What is the justification for associating ALS with proliferation of nicotinic ACh receptors? We have already noted that Rowland (5) claims that fasciculation tends to characterize ALS. On the other hand, agents which block the nicotinic ACh receptor can abolish fasciculations, and neostigmine (a cholinesterase inhibitor) can cause fasciculations (8). Thus if fasciculations can be prevented by inhibition of ACh reception and caused by enhancement of ACh reception, then both ALS and fasciculations might be associated with proliferation of nicotinic ACh receptors. Even if a typical case of ALS is associated with enhanced release of ACh from axon terminals at the neuromuscular junction or with proliferation of ACh
1. Rosen D R, Siddique T, PattersonD et al. Mutationsin Cu/Zn superoxide dismutase gene are associated with familial amyatrophic lateral sclerosis. Nature 1993; 362: 59-62. 2. McNamara J 0, Fridovich I. Did radicals strike Lou Gehrig? Nature 1993; 362: 20-21. 3. Appel S H, Engelhardt J I, Garcia J, Stefani E. Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiolbgicai abnormalities to the neuromuscular junction. Proc Natl Acad Sci USA 1991: 88: 647-651. 4. Appel S H. Excitotoxic neuronal cell death in amyotrophic lateral sclerosis. Trends Neurosci 1993; 16: 3-5. 5. Rowland L P. Ten central themes in a decade of ALS research. In: Rowland L P, ed. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. New York: Raven Press, 1991: 3-23. 6. Kandel E R. Nerve cells and behaviour. In: Kandel E R, Schwartz J H, Jessell T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991: 18-32. 1. Rowland L P. Diseases of chemical transmission at the nervemuscle synapse: myasthenia gravis. In: Kandel E R, Schwartz J H, Jesse11T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991; 235-243. 8 Rowland L P. Diseases of the motor unit. In: Kandel E R, Schwartz J H, Jesse11T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991: 244-257. 9 Roitt I M. Essential Immunology. 7th ed. Oxford: Blackwell Scientific Publications 1991: 340.
Amyotrophic Lateral Sclerosis: Hypothetical Pathogenesis D. W. BROWN 55 Smyma Powder Springs Road SE, Marietta, GA 30060, USA.
Abstract - A hypothetical pathogenesis for a typical case of amyotrophic lateral sclerosis (ALS) follows from opinions of Rowland and results of neuroscientists at Baylor. ALS might typically result from an autoimmune disorder that causes IgG to enhance release of acetylcholine (ACh) from axon terminals. Motor neuron overactivity associated with fasciculation might result from enhanced release of ACh which is taken up by nicotinic ACh receptors. Increased levels of intracellular calcium ions might result from motor neuron overactivity associated with fasciculation. Neuronal cell degeneration and death might result from increased levels of intracellular calcium ions.
Hypothetical
pathogenesis
Rosen et al (1) demonstrate that familial variants of amyotrophic lateral sclerosis (ALS) are linked to mutations in the gene which encodes cytosolic superoxide dismutase (SODl), an enzyme essential for the elimination of toxic superoxide anions; however, only about 10% of ALS cases are of the familial type. McNamara and Fridovich (2) suggest how the decrease of SOD1 activity might explain the excitotoxic mechanisms of motor neuron death. What might be the pathogenesis of the typical case of nonfamilial ALS? Immunoglobulin (Ig) G from ALS patients can enhance release of acetylcholine (ACh) from axon terminals at the neuromuscular junction (3). Neuronal cell degeneration and death in ALS (as well as ischemia/hypoxia and hypoglycemia) are related to increased levels of intracellular calcium ions (4). Rowland (5) claims that fasciculation is a sign of disorder of the perikaryon and that both fasciculation and fibrillation tend to occur where there is disorder
of the perikaryon and the peripheral nerve; clinical fasciculation is evident in some sensorimotor neuropathies, but everyday clinical experience indicates that fasciculations rarely occur in sensorimotor neuropathies. When neurons fire repeatedly, potassium ions accumulate in the extracellular space; astrocytes, because of their high permeability to potassium ions, can take up and store the excess potassium ions so as to protect the neighboring cells from excessive membrane depolarization (6). If motor neuron overactivity is prolonged, then the astrocytes might fail to adequately buffer the excess potassium ions; in ALS, the proliferation of astrocytes might be correlated with accumulation of potassium ions in the extracellular space. Motor neurons have voltage-gated calcium channels that open in response to membrane depolarization. Researchers originally assumed that in ALS the voltage-gated calcium channels are the channels through which excess calcium ions enter the motor neurons; more recent studies have suggested that in
Date received 7 October 1993 Date accepted 20 December 1993
393
394
MEDICAL HYPOTHESES
ALS a pathogenically important part of the calcium ion influx also occurs via ligand-gated calcium channels (4). As neuronal activity increases, neurons release more potassium ions and receive more calcium ions. Thus, motor neuron overactivity which is associated with fasciculation might cause high levels of intracellular calcium ions. If the presence of fasciculations really does tend to distinguish ALS from peripheral neuropathy (PN), then increased levels of intracellular calcium ions might typically result from two distinct types of motor neuron overactivity in ALS and PN. One type of overactivity would be associated with fasciculation in ALS and with enhanced release of ACh, and another type of overactivity would be associated with fibrillation in PN and with increased activation of voltage-gated calcium channels. If the typical case of ALS results from an autoimmune disorder, then it might be instructive to consider two other autoimmune disorders: myasthenia gravis and Lambert-Eaton syndrome. Myasthenia gravis is typically an autoimmune disorder in which antibodies are produced against the nicotinic ACh receptor; whereas, Lambert-Eaton syndrome is attributed to the presence of antibodies to voltagegated calcium channels in the presynaptic terminal (7). Consider a hypothetical table:
receptors, there might be many exceptions even for nonfamilial ALS cases. Also, enhanced release of ACh might have a variety of causes. Conclusion This communication offers speculation that ALS IgG leads to enhanced release of ACh; the consequent increase in motor neuron activity then causes increased levels of intracellular calcium ions and eventual cell death. If the preceding speculation is true, then ALS might respond favorably to agents which block the nicotinic ACh receptor. Even if the preceding speculation is false, Appel’s view (4) of the role of intracellular calcium ions in neuronal degeneration and of the role of the interaction of ALS IgG with voltagegated calcium channels would imply that autoimmune disorders might account for most cases of nonfamilial ALS. Are immunosuppressive drugs the best therapy for the typical case of ALS? It is conceivable that the thymus contains ACh receptors in a particularly antigenic form (9). Antibodies against nicotinic ACh receptors might cause a primary enhancement of ACh release or a secondary proliferation of ACh receptors. Is thymectomy an effective therapy for ALS in a significant percentage of cases? References
Nicotinic ACh
receptors Blockade Proliferation
Voltage-gated calcium channels
myasthenia gravis Lambert-Eatonsyndrome one form of ALS one form of PN
What is the justification for associating ALS with proliferation of nicotinic ACh receptors? We have already noted that Rowland (5) claims that fasciculation tends to characterize ALS. On the other hand, agents which block the nicotinic ACh receptor can abolish fasciculations, and neostigmine (a cholinesterase inhibitor) can cause fasciculations (8). Thus if fasciculations can be prevented by inhibition of ACh reception and caused by enhancement of ACh reception, then both ALS and fasciculations might be associated with proliferation of nicotinic ACh receptors. Even if a typical case of ALS is associated with enhanced release of ACh from axon terminals at the neuromuscular junction or with proliferation of ACh
1. Rosen D R, Siddique T, PattersonD et al. Mutationsin Cu/Zn superoxide dismutase gene are associated with familial amyatrophic lateral sclerosis. Nature 1993; 362: 59-62. 2. McNamara J 0, Fridovich I. Did radicals strike Lou Gehrig? Nature 1993; 362: 20-21. 3. Appel S H, Engelhardt J I, Garcia J, Stefani E. Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiolbgicai abnormalities to the neuromuscular junction. Proc Natl Acad Sci USA 1991: 88: 647-651. 4. Appel S H. Excitotoxic neuronal cell death in amyotrophic lateral sclerosis. Trends Neurosci 1993; 16: 3-5. 5. Rowland L P. Ten central themes in a decade of ALS research. In: Rowland L P, ed. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. New York: Raven Press, 1991: 3-23. 6. Kandel E R. Nerve cells and behaviour. In: Kandel E R, Schwartz J H, Jessell T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991: 18-32. 1. Rowland L P. Diseases of chemical transmission at the nervemuscle synapse: myasthenia gravis. In: Kandel E R, Schwartz J H, Jesse11T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991; 235-243. 8 Rowland L P. Diseases of the motor unit. In: Kandel E R, Schwartz J H, Jesse11T M, eds. Principles of Neural Science, 3rd ed. New York: Elsevier, 1991: 244-257. 9 Roitt I M. Essential Immunology. 7th ed. Oxford: Blackwell Scientific Publications 1991: 340.