Accelerated and widespread neuronal loss occurs in motor neuron degeneration (mnd) mice expressing a neurofilament-disrupting transgene.
To examine the effects of multiple stressors on the onset and specificity of a neurodegenerative disease, we derived mnd/mnd mice expressing a neurofilament-H/lacZ transgene. The mnd mutation causes adult-onset motor dysfunction, and produces abnormal ubiquitous accumulation of autofluorescent lipopigment, with retinal degeneration and late-onset motor neuron degeneration. The neurofilament H-beta-galactosidase fusion protein causes endogenous neurofilament subunits to precipitate in perikarya, but shows neither significant neuronal degeneration nor behavioral changes until advanced age. In mnd/mnd-transgenic animals, neurological symptoms, lipopigment accumulation, and motor neuron loss were substantially accelerated. Newly vulnerable populations of neurons also degenerated, including cerebellar Purkinje cells and dorsal roots. This study exemplifies a synergistic interaction between a neuron-specific and a ubiquitous defect, leading to significant neurological consequences. It further indicates that cytoskeletal abnormalities similar to those observed in late-onset human neurodegenerative disorders can interact with other cellular defects and contribute to pathogenesis.
Plummer
J
J
Wadsworth Center for Labs and Research, New York State Department of Health, Albany, New York 12201, USA.
Peterson
A
A
Messer
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009186:Myelin Sheath / Q000502:physiology / Q000648:ultrastructure; D009410:Nerve Degeneration; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D016900:Neurofilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology; D001616:beta-Galactosidase / Q000096:biosynthesis
D016900:Neurofilament Proteins; D011993:Recombinant Fusion Proteins; C051774:neurofilament protein H; D001616:beta-Galactosidase