Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease

Abstract

Niemann Pick disease is a family of autosomal recessive disorders characterized by cholesterol accumulation. The most common type is Niemann Pick type A/B (NPA/B), resulting from deficient acid sphingomyelinase activity, which leads to sphingomyelin and cholesterol accumulation. The neuropathology of NPA/B includes widespread neuronal degeneration. An acid sphingomyelinase knockout mouse model of NPA/B (ASMKO) has been developed by the targeted deletion of the acid sphingomyelinase gene. When cerebellar morphology was examined in the ASMKO mouse at postnatal day 60 (P60), a dramatic pattern of longitudinal stripes was revealed in which roughly half the Purkinje cells had died, leaving a highly stereotyped, bilaterally symmetrical array of stripes. Antizebrin II immunocytochemistry revealed that the absent Purkinje cells corresponded exactly to the zebrin II-negative subset, leaving the zebrin II-positive subset apparently intact. By P120, some of the zebrin II-positive Purkinje cells had also been eliminated from the posterior vermis and hemispheres. By P180, all Purkinje cells had been lost from the anterior lobe. Finally at P240, almost all Purkinje cells had disappeared to leave a stereotyped distribution in lobules VI, IX-X and the flocculus and paraflocculus. The temporal pattern of Purkinje cell death demonstrates differential susceptibility of morphologically identical cells that appear to be linked to their molecular phenotypes.

A Mutation inAf4Is Predicted to Cause Cerebellar Ataxia and Cataracts in the Robotic Mouse

“…Three central bands of resistant cells and preferential loss of Purkinje cells in the anterior cerebellum with sparing of lobe X have been described in the leaner mutant (Herrup and Wilczynski, 1982) and in the mouse models of NiemannPick disease types A/B [acid sphingomyelinase knock-out (ASMKO)] and C (Higashi et al, 1993;Sarna et al, 2001). These changes are preceded by granule cell loss in the leaner mouse (Herrup and Wilczynski, 1982;Heckroth and Abbott, 1994), distinguishing the pathological findings from those seen in robotic mutants.…”

“…These changes are preceded by granule cell loss in the leaner mouse (Herrup and Wilczynski, 1982;Heckroth and Abbott, 1994), distinguishing the pathological findings from those seen in robotic mutants. However, the similarity of the region-specific cell loss in robotic mice to the Niemann-Pick models is more striking, and dot-like ubiquitin staining has also been noted in the type C disease model (Higashi et al, 1993;Sarna et al, 2001).…”

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

“…An absence or deficiency of functional ASM protein results in lysosomal accumulation of sphingomyelin, and subsequent secondary metabolic defects such as abnormal cholesterol accumulation (7,20). Cholesterol buildup in the ASMKO mouse brain can be visualized by using filipin, an autofluorescent molecule isolated from Streptomyces filipinensis.…”

Whole-mount Immunohistochemistry: A High-throughput Screen for Patterning Defects in the Mouse Cerebellum

“…Previous studies have shown zebrin II IHC to be a powerful tool. Its expression reflects the fundamental molecular architecture of the cerebellum and is sensitive to genetic manipulations of cerebellar development [e.g., Lc/ϩ (Tano et al 1992); weaver (Eisenman et al 1998); disabled (Gallagher et al Figure 3) or patterns of Purkinje cell death [e.g., the acid sphingomyelinase null (ASMKO) mouse (Sarna et al 2001)] but insensitive to secondary influences such as general health status, age, or gender. It is highly reproducible among individuals, is insensitive to the genetic background against which a mutation is seen, and is accurately quantifiable, both for the number of stripes and their widths.…”