Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder involving progressive loss of motor function. Better known as Lou Gehrig's disease, ALS tends to begin in middle age. Patients usually die of pulmonary complications after a highly variable duration of illness, averaging three years. Because of ALS's tragic toll on the victim and the family, considerable human and animal research has been directed toward improving our understanding and treatment of ALS. The most widely used animal models are the wobbler mouse and hereditary canine spinal muscular atrophy (HCSMA) in the Brittany spaniel. While these models have been studied quite extensively, their value in assisting ALS management is questionable.
Background: Human ALS
ALS is characterized by degeneration of the anterior horn cells, the corticospinal tracts, and sometimes the corticobulbar tracts. Patients suffer atrophy, weakness, and fasciculations, and they may have dysphagia and dysarthria. Patients generally do not experience sensory system impairment, ophthalmoplegia, or dementia.(1)
Part 1: Comparison of the Animal Models to Human ALS
1) Wobbler Mouse
Clinical Presentation
Wobbler mice have degeneration of lower motor neurons, as in ALS. These mice also have significantly fewer large myelinated fibers than normal mice, but not significantly fewer small fibers -- features that Mitsumoto and Bradley have termed "identical" to those found in ALS.(2) Despite some similarities, however, there are numerous differences in pathology and natural history between ALS and the wobbler mouse syndrome. While ALS involves upper and lower motor neurons, wobbler mice have only lower motor neuron disease. Muscle weakness in wobbler mice is largely restricted to the neck and forelimbs, with sparing of the hindlimbs.(3) In contrast, ALS patients experience cranial nerve impairment and loss of motor neurons to the lower extremities and the respiratory muscles.
A distinctive feature of ALS is a pattern of neuronal loss known as "dying back."(4,5) This process has nbt been found in wobbler mice.(2,3) Similarly, neurofilamentous axonal swellings, which may be critical to the disease process,(1) are rarely present in wobbler mice.(3) Furthermore, whereas wobbler mice suffer "vacuolar degeneration in the granular endoplasmic reticulum,"(1) vacuolar degeneration is not seen in ALS.(5)
Pathogenesis
Wobbler mice have an autosomal recessive motor neuron disease.(3) In contrast, only about 10% of ALS is inherited, and in these cases its transmission appears to be autosomal dominant.(1) While little is known about underlying degenerative processes in wobbler mice and humans, differences in genetics and clinical presentation cast doubt on the view that the two conditions' pathogeneses are similar.
2) Hereditary Canine Spinal Muscular Atrophy (HCSMA) Clinical Presentation
Both ALS and HCSMA feature loss of large spinal cord motor neurons and axonal swellings with neurofilaments.(6-8) While claiming that the HCSMA model resembles ALS, Hirano et al. have cautioned that differences between the two diseases raise doubts about this animal model's value:
Of all the animal models, the accelerated hereditary canine spinal muscular atrophy described by Cork et al is the most reminiscent of human ALS. This condition selectively involves the lower motor neurons and shows chromatolysis in addition to the more prominent neurofilamentous accumulations. While the fine structure of these accumulations is quite reminiscent of those seen in the present study (of ALS), several important differences must be noted. Firstly, the prominence of the neurofilamentous accumulations in the dog model is far beyond that which we see in the human. Secondly, in the dog model connections between filament-filled processes and the soma are apparently common, whereas they could not be visualized in our study. Carpenter and Hirano and, recently, Kurisaki et al published illustrations of this phenomenon in human ALS. This difference may reflect a significantly different position of the filamentous accumulation in the human axons. Thirdly, polyglucosan bodies, honeycomb-like structures, ribosome-associated linear structures and spiky mitochondria have not been reported in the dog model.
In addition, other differences, not related to the filamentous accumulations, exist between the dog model and human ALS. In typical human ALS, the upper motor neuron system is also involved, unlike in the dog. Human ALS also shows Bunina bodies which have not been described in the dog. Nevertheless., the usefulness of the dog model for an understanding of human ALS must not be discounted. How appropriate it is as a model for human ALS is still to be determined?
In reviewing ALS pathology, Tandan and Bradley have noted the rarity of motor neuron vacuolation, "except in rapidly progressive disease."(5) In contrast, this degeneration is seen in HCSMA dogs.(10)
Pathogenesis
The underlying degenerative process of HCSMA, like that of ALS, remains largely unknown. About 90% of ALS cases are sporadic and 10% are thought to be inherited in an autosomal dominant fashion. All cases of HCSMA have autosomal dominant inheritance. HCSMA shares many features with human ALS, but the biochemical bases of these two conditions appear to differ.(1)
Part 2: Clinical Review Articles
Two recent comprehensive ALS overviews by investigators who have done both human and animal model studies include extensive discussions of animal research.(1,5,10) The first part of Tandan and Bradley's review, which covers clinical features, pathology, and ethical issues in ALS management, contains no reference to animal research.(5) The second part, on etiopathogenesis, contains several references to animal research, including the following: "Transmission studies . . . utilizing multiple tissue specimens (always including brain) from Guamanian patients and patients with the sporadic type of ALS, have, to date, been negative and fail to support the view that ALS is a slow viral infection."(10) These negative findings, however, do not eliminate the possibility of a viral infection, because some viruses are virulent only for humans. Tandon and Bradley remark that the slowed axonal transport found in wobbler mice and HCSMA dogs suggests "a similar impairment in ALS."(10) Until methods to study axoplasmic flow are developed in humans, however, this theory will remain mere speculation. Finally, the authors acknowledge, "Lymphocyte capping, which is an index of membrane fluidity and cytoskeletal preservation, is increased in the wobbler mouse, but normal in patients with sporadic or familial types of ALS."(10)
Tandan and Brandley summarize, "Animal models enable us to study the temporal and spatial evolution of diseases . . . and thus these studies using animal models yield better perspectives on the pathogenesis of human disorders. Unfortunately, no animal model reproduces all the salient features of ALS."(10)
Although they also discuss animal models in detail, Mitsumoto et al. do not credit animal models with specific contributions to our understanding or treatment of ALS. They merely suggest that motor neuron degeneration in the animals might be similar to neuronal loss in ALS. Their conclusions are similar to those of Tandan and Bradley: "Although the biochemical causes of MND (motor neuron disease) in animal models most likely differ from those in human MND, these naturally occurring animal models provide us with a better understanding of disease mechanisms involving the fundamental processes of motor neuron degeneration and repair."(1)
Neither review article credits the animal models with important contributions to our understanding of ALS. Both note theories of pathogenesis based on animal models, but these theories need to be confirmed for human ALS. Both papers encourage continued research with the models. The authors maintain that these animal models can reveal mechanisms of neuronal degeneration that are relevant to humans. The differences between these models and ALS, however, raise doubts that the etiopathology of disease in either of the models is similar to that of ALS.
Interestingly, Rowland, in an editorial review on the cause of ALS, does not mention either animal model.(11) He does discuss the inability to transmit ALS to.(11) [sic]
Finally, Eisen and Hudson, reviewing a symposium on ALS pathogenesis, do not mention any animal models of ALS.(12)
Part 3: Clinically Important Questions
There is no effective therapy for ALS. Mitsumoto et al. contend, "It is possible that specific treatment of ALS will become available only after the pathogenesis is discovered, but therapeutic trials could also provide clues to the etiology of this disorder." A better understanding of ALS pathogenesis would certainly assist the development of therapeutic interventions. Consequently, a critical question is, "What is the cause of ALS?" Extensive epidemiological research has addressed ALS etiopathology.(13,14) Studies of human "models" of ALS have included Guam disease(15,16) and poliomyelitis.(11) Other studies using tissues from ALS patients may yield clues. For example, Mitsumoto et al. have written, "Analysis with individual immunoglobulins has revealed that in ALS both IgG and IgA have specific effects on erythrocyte fragility, supporting the idea that ALS is an autoimmune disease."(1) Similarly, Manetto et al. used tissues obtained at autopsy to show that phosphorylation of neurofilaments is altered in ALS.(17) In addition, new non-invasive imaging technologies, such as MRI scans,(18) permit study of ALS before the disease's terminal stages.
Because neither wobbler mice nor HCSMA dogs have ALS, it is difficult for them to provide new insights into ALS. The relevance of any finding needs clinical verification; this limits the animal research's utility. Our current understanding of ALAS is based largely on human clinical investigation. Animal models have done little to assist the search for the cause(s) of ALS.
A second clinically important question is, "What therapeutic modalities would assist ALS patients?" It will be difficult, if not impossible, to develop animal models that may help direct clinical trials before we understand the basic pathology in human ALS. Contemporary animal models differ significantly from human ALS, and it appears tenuous to base clinical research on results of therapeutic interventions with these animals.
Conclusions
Animal models may increase our basic understanding of neuronal degeneration mechanisms. Whether degenerative processes in these animals are similar to ALS or any other human condition, however, is not known. Wobbler mice and HCSMA dogs appear to suffer from a condition quite dissimilar to ALS. While wobbler mice, HCSMA dogs, and ALS patients all have motor neuron degeneration, there are marked differences in clinical presentation and histopathology. In terms of pathogenesis, the animal models represent genetic diseases, but ALS rarely has a family history. The cause of ALS motor neuron loss, currently a mystery, appears to differ from that in these animal models. The development of effective ALS therapies will probably require an understanding of ALS etiopathology, but the animal models are of doubtful value in addressing this critical issue.
References
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