Purkinje cell degeneration, a new neurological mutation in the mouse.

Abstract

A new autosomal recessive mouse mutation, Purkinje cell degeneration (ped), is described. Mutants exhibit a moderate ataxia beginning at 3 to 4 weeks of age. The ataxia results from postnatal degeneration of virtually all cerebellar Purkinje cells beginning around 15 to 18 days of age and progressing rapidly over the next 2 weeks. In addition to the cerebellar disease there is slow progressive degeneration in the retina (photoreceptor cells) and olfactory bulb. Also, adult males have abnormal sperm.Because of the uniform, stereotyped, and relatively simple organization of the cerebellar cortex many neuroscientists have chosen to study its functional organization (1), cytology and synaptic architecture (2), or development (3). Since the most obvious functions of the cerebellum involve posture and motor coordination, most mutations will affect behavior and are readily detected. In mice, a number of cerebellar mutants have been described (4) MATERIALS AND METHODSThe pcd mutation occurred in the C57BR/cdJ strain at The Jackson Laboratory. Because of the poor breeding performance of this strain, pcd/pcd females were mated to C3H/ HeJ males and the Fj-animals were intercrossed to produce pcd/pcd F2 females. These females were then crossed back to C57BR/cdJ males and the pcd mutation was maintained thereafter by brother-sister matings. The mutant gene is also being transferred to the C57BL/6J strain. The animals used in this study came from both lines.For histological studies, the mice were fixed by perfusion through the heart with 1% formaldehyde and 1.25% glutaraldehyde in 0.1 M sodium phosphate buffer, pH 7.2. The brains were removed, dehydrated, and embedded in either paraffin or celloidin. Sections were cut at 7 or 20 gm and stained with cresyl violet. In addition, pieces of cerebellum and eyes were postfixed in OS04, dehydrated, embedded in an Epon-Araldite mixture, and sectioned at 1 Am, and the sections were stained with toluidine blue.The various brain regions are designated according to the atlas of Sidman et al. (14). Day of birth is considered day 0.To determine if there was any difference in body weights between mutants and controls, all young in 8 litters were earmarked on day 15

Mifepristone (RU486) protects Purkinje cells from cell death in organotypic slice cultures of postnatal rat and mouse cerebellum

“…Newborn (P0) mice of three litters issued of the mating of heterozygous pcd mutant mice (10,11) were also used in this study. Three independent pcd mutations arose spontaneously, but, although the gene Nna1 has been identified as the mutated pcd gene (13), only two pcd strains can be identified by PCR.…”

“…Using both agonists and antagonists of GR and PR, PR mutant mice (PR-KO) and brain specific GR mutant mice (9), as well as potent antioxidant agents we show that the neuroprotective activity of RU486 is independent of its antagonistic properties at PR or GR, and that it is not related to an antioxidant activity. A model of neurodegenerative cell death, i.e., Purkinje cell degeneration (pcd), an autosomal recessive mutation in the mouse, causing the death of all cerebellar Purkinje cells between the second and fourth postnatal weeks (10,11), was also used in this study. We demonstrate that the steroid RU486 highly promotes survival of Purkinje cells in organotypic cultures of cerebellar slices from newborn (P0) pcd mutants mice.…”

Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndrome

“…Many studies have therefore focused on different ways to decrease PC loss in FAS (7,8). However, different models of ataxia that result from PC death per se (pcd mice, SV4 mice, T147 transgenic mice) have demonstrated that considerable neuropathology can occur without the manifestation of a neurological phenotype and that ataxia occurs in mice only after there is loss of 50-75% of the PCs (9)(10)(11). Because FAS models are characterized by a nonprogressive loss of only 20% of PCs, the presence of an associated neuronal dysfunction can contribute to the observed ataxic phenotype.…”

A missense mutation in AGTPBP1 was identified in sheep with a lower motor neuron disease

“…Similar to other cytosolic carboxypeptidases, the mouse Nna1 protein is broadly expressed in the brain, pituitary, eye, testis and other tissues (Kalinina et al, 2007). Mutations or abnormal expression of Nna1 have been found to cause a pcd phenotype in mice characterized by degeneration of Purkinje cells, mitral cells of the olfactory bulb, thalamic neurons and retinal photoreceptor cells as well as degeneration of sperm (Fernandez-Gonzalez et al, 2002, Mullen et al, 1976. A total of 12 alleles in mouse mutants related to Agtpbp1 have been summarized by the Jackson Laboratory (http:// www.informatics.jax.org/searches/allele_report.cgi?_Marker_key=79447).…”