Mutant mouse models of ALS

Abstract

THERE are three major mouse models of ALS in the current literature. Two early onset models show vacuolar pathology, while the late-onset motor neuron degeneration (mnd) shows inclusions, increased lysosomal, and nonlysosomal hydrolases and rearrangement of neurofilaments. All models may be useful in determining motor neuron-specific vulnerability. Additional late-onset models may be particularly valuable for examination of delayed or gradual neuronal degenerations. Animal models of neurodegenerative disease offer opportunities for the study of aspects of the etiology that are not available from purely clinical studies. Such studies can then progress readily to investigation of drug efficacy and mechanisms. Mutant mouse models are particularly attractive in that they are backed by strong genetics. There are also several highly inbred backgrounds available, plus several wild mouse strains which have been bred to genetic homogeneity. These should allow the study of modulators of the primary effects of genes for neurological disease. Because mice are small and age quickly, it is economically feasible to keep substantial numbers of them. In a well-defined genetic disease, the gene acts as a reproducible perturbant; thus, it is possible to study each stage of the disorder from presymptomatic on. This is useful for developmental disorders and is especially valuable for delayed neuronal degenerations. Identification of cognitive defects in mice presents difficulty; however, a large number of motor diseases are readily recognized by progressive neurological dysfunction (3). Two early onset autosomal recessive motor neuron diseases in mouse mutants have been studied in detail, wobbler (wb) and wasted (wst) rev. in (6). Both show vacuolar pathology in motor neurons and onset during the first 3 weeks after birth. The former shows forelimb involvement, affecting predominantly soma of the cervical motor neurons. The rate of axonal transport and the number of neurofilaments are greatly reduced in affected cells (11) and there is a selective reduction in the regenerative capacity of these cells as well (12). In addition to vacuolar pathology, the wst mutants show accumulations of phosphorylated 200 kDa neurofilamerit immunoreactive protein in motor neurons in the anterior horn of the spinal cord and the brainstem cranial nuclei by 30 days of age (5). Tremor appears to involve all four limbs, although the paralysis was reported to affect mainly the hindlimbs, with wasting and death by Day 31. This mutant strain also develops reduced secretory immune responses and shows abnormal DNA repair mechanisms. (An endogenous retrovirus has been postulated as a mechanism of action for both the immune and neurological defects, based on preliminary data (5).) While wst, wb, and a new nonvacuolar early onset recessive motor neuron disease (an insertional mutation; M. Meisler, pers. comm.) may seem irrelevant to adult-onset ALS, it is probably worthwhile to examine aged and stressed heterozygotes of these recessives for signs of a semidominant effect, or delayed neuronal degeneration. The late-onset mutation Motor neuron degeneration (mnd)