Spontaneous Murine Neuroaxonal Dystrophy: a Model of Infantile Neuroaxonal Dystrophy
Introduction
Inherited, primary or endogenous neuroaxonal dystrophies (NADs) form a group of debilitating and ultimately fatal neurodegenerative diseases affecting human beings (Vuia, 1977, Williamson et al., 1982, Kimura et al., 1987, Taylor et al., 1996) and animals, including horses, cats, rats, several breeds of dog (Cork et al., 1983, Schmidt et al., 1983, Chrisman et al., 1984, Carmichael et al., 1993, Sacre et al., 1993, Franklin et al., 1995, Adams et al., 1996) and several inbred and genetically engineered mouse strains (Yamazaki et al., 1988, Dal Canto and Gurney, 1994, Schmidt et al., 1998, Dragatsis et al., 2000, Liedtke et al., 2002, Matsushima et al., 2005). The characteristic pathological feature of NAD in all species is the swollen axon or “spheroid”, often found throughout the central and peripheral nervous systems (Summers et al., 1995). The term “spheroid” refers non-specifically to swollen axons seen by light microscopy and does not describe the nature of the underlying axonal damage or distinguish between potential causative mechanisms. Although spheroids develop in all variants of endogenous NADs, differences in age of onset, clinical manifestations, and distribution of lesions separate one form from another (Vuia, 1977, Williamson et al., 1982, Kimura et al., 1987, Taylor et al., 1996). A number of neuropathological conditions including infectious, demyelinating, toxic or traumatic injuries can damage normal axons and produce spheroids. At the ultrastructural level, however, these “secondary” spheroids are seen to differ greatly from the spheroids found in primary axonopathies or endogenous NAD; thus, degenerate axons predominate in secondary axonopathies and consist of electron-dense bodies, whereas the spheroids in primary axonopathies contain organelles and structural elements that accumulate as a result of defects in axonal transport (Lampert, 1967, Koestner and Norton, 1991, Summers et al., 1995). Although similar lesions are seen in various mammalian species with spontaneously occurring NAD, appropriate animal models for studying the natural progression, biochemical composition and possible underlying mechanisms of spheroid formation are limited.
A new and potentially valuable mouse model of endogenous NAD arose from a spontaneous mutation in a congenic mouse strain, C.D2 Es-Hba (HBA). This strain contained <5% of the DBA/2 genome on the BALB/c mouse strain background and was originally bred to map susceptibility to lymphomagenesis, and subsequently utilized to study immune responses to antigen stimulation in models of atopy and asthma (Ruscetti et al., 1985, McIntire et al., 2001). In the course of these studies, which utilized thousands of HBA-derived progeny for positional cloning of a T-cell and airway hyperreactivity locus, mice were identified with clinical signs of hindlimb spasticity, mild ataxia and progressive paraparesis. The trait appeared to be hereditary, as it segregated within certain HBA sublines. This interesting neurological phenotype was investigated in the present study. Characterization of the neurological disease progression with ultrastructural and immunohistochemical analyses was performed to document similarities between the disease in these mice and human NAD, of which infantile neuroaxonal dystrophy (INAD) is one variant.
Section snippets
Animals
The congenic mouse strain, C.D2 Es-Hba, which contains <5% of the DBA/2 mouse strain genome, was originally produced by crossing BALB/c with DBA/2 mice, followed by backcrossing for 10 generations on to the BALB/c mouse strain. Mice were bred and representative progeny with the clinical phenotype were examined histologically, immunohistochemically and ultrastructurally at various stages of disease progression. All studies were approved by Stanford's Institutional Animal Care and Use Committee
Animals
The NAD trait was originally identified in <2% of the HBA offspring, but it was observed that affected litters usually contained more than one affected animal. Healthy siblings of affected animals were selected from the HBA colony, and subsequent breeding of these HBA sublines produced approximately equal numbers of males and females. In crosses that produced mice with NAD, approximately 25% of the offspring (representing over 100 litters) were clinically affected, suggesting an autosomal
Discussion
The NAD mouse provides a potentially useful model for the study of endogenous human NAD, particularly in view of the parallels in ultrastructural pathology. The advantages of such an animal model over the use of human autopsy specimens are numerous. It enables nervous tissue to be examined before the onset of severe clinical signs, thus providing insight into pathogenesis. Moreover, it enables both primary disease progression and secondary lesion development to be investigated.
Many previous
Acknowledgments
The authors thank Pauline Chu for expert technical assistance in histology and immunohistochemistry, Nafisa Ghori for electron microscopy, Elana Hadar for care and management of the NAD mouse colony, Dr Linda Cork for critical neuropathological advice, and the Department of Comparative Medicine for support of the mouse colony. This work was funded in part by the R.J. Murdock Foundation.
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