An Early-Onset Congenic Strain of the motor neuron degeneration (mnd) Mouse Anne Messer, 1 Kevin Manley, and Julie A. Plummer Wadsworth Center, New York State Department of Health, Albany, New York 12201; and Department of Biomedical Science, Albany, New York 12201 Received January 21, 1999 The mouse mutant motor neuron degeneration (mnd/mnd) has been proposed as a model of neuro- nal ceroid lipofuscinosis (NCL) on the basis of wide- spread abnormal accumulating lipopigment and neuronal and retinal degeneration. Clinically, the mutant on a C57Bl/6 genetic background shows a progressive motor abnormality starting by 6 months of age, with death prior to 12 months. When mnd is outcrossed to the AKR/J genetic back- ground, ca. 40% of the mnd/mnd F2 progeny show early onset (onset by 4.5–5 months and death by 7 months). A congenic strain of mnd has now been produced by eight generations of backcross onto the AKR background. Mice on this background show average onset at 4 months, and most are mor- ibund prior to 5.5 months. The early onset appears to correlate with levels of abnormal accumulating material, and should prove useful in elucidating NCL neurodegenerative mechanisms. © 1999 Academic Press Key Words: neuronal ceroid lipofuscinosis; Bat- ten’s disease; motor neuron degeneration. On the C57Bl/6J (B6) genetic background, the motor neuron degeneration (mnd/mnd) mouse shows an adult-onset hereditary neurological disease, with motor abnormality recognizable by 6 months of age, progressing to severe spastic paralysis and prema- ture death at 10 –12 months (1). Many facets of this disease model aspects of human neuronal ceroid li- pofuscinosis (NCLs), a heterogeneous group of neu- rodegenerative disorders characterized by blind- ness, seizures, ataxia, dementia, and premature death (2,3). A survey of histopathology with Nissl stains shows widespread disruption of cellular in- tegrity in many brain areas as the disease progresses (4). Many neurons also show cytoskeletal disruption, with neurofilaments marginated in the cell soma (5), increased immunoreactive ubiquitin (6) and cyto- plasmic inclusions that are positive for protein, car- bohydrate, and lipid stains, with greatly increased -glucuronidase (7). Studies using genetic chimeras and mnd/mnd fibroblasts in culture have shown that the mnd gene is acting intrinsically in all cells (8). Autofluorescence can be seen as early as the first month, in a variety of neural and nonneural tissues. Both the number of cells affected and the amount of autofluorescence within individual cells increase dramatically as the mnd mice age (9). Bronson et al. (10) and Pardo et al. (11) have described NCL-like inclusions and accumulating mitochondrial ATP synthase subunit c (subunit c) in these mice similar to those found in human NCL (12–14) and in sheep and dog models (15–17). Retinal degeneration also begins in the first month (18). The mnd gene maps to proximal chromosome (Chr.) 8 (19), between regions that are syntenic to human chromosomes 8p11 and 13q34. Surprisingly, when mnd is outcrossed to the AKR background, ca. 40% of the mnd/mnd F2 progeny show early onset (onset by 4.5–5 months and death by 7 months). This accelerated timing effect seems to be strain specific and unlinked to the mnd gene itself (19,20). We have therefore produced a congenic strain of mnd on the 1 To whom correspondence should be addressed at the David Axelrod Institute, Wadsworth Center, New York State Depart- ment of Health, New Scotland Avenue, P.O. Box 22002, Albany, NY 12201–2002. Fax: (518) 474 –3181. Molecular Genetics and Metabolism 66, 393–397 (1999) Article ID mgme.1999.2817, available online at http://www.idealibrary.com on 393 1096-7192/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.