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

Niemann Pick disease is a family of autosomal recessive disorders character ized by cholesterol accumulation. The most common type is Niemann Pick type A/B (NPA/B), resulting from deficient acid sphingomyelinase activity, whic h leads to sphingomyelin and cholesterol accumulation. The neuropathology o f NPA/B includes widespread neuronal degeneration. An acid sphingomyelinase knockout mouse model of NPA/B (ASMKO) has been developed by the targeted d eletion of the acid sphingomyelinase gene. When cerebellar morphology was e xamined 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 s tripes. Antizebrin II immunocytochemistry revealed that the absent Purkinje cells corresponded exactly to the zebrin II-negative subset, leaving the z ebrin 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 anterio r lobe. Finally at P240, almost all Purkinje cells had disappeared to leave a stereotyped distribution in lobules VI, IX-X and the flocculus and paraf locculus. The temporal pattern of Purkinje cell death demonstrates differen tial susceptibility of morphologically identical cells that appear to be li nked to their molecular phenotypes.