Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease

Niemann Pick disease type C1 (NPC1) is an inherited, autosomal recessive, lipid-storage disorder with major neurological involvement. Purkinje cell death is a prominent feature of the neuropathology of NPC. We have investigated Purkinje cell death in two murine models of NPC1, BALB/c npc(nih) and C57BLKS/J spm. In both cases, extensive Purkinje cell death was found in the cerebellum. The pattern of Purkinje cell death is complex. First, zebrin II-negative Purkinje cells disappear, to leave survivors aligned in stripes that closely resemble the pattern revealed by using zebrin II immunocytochemistry. Subsequently, as the disease progresses, additional Purkinje cells die. At the terminal stages of the disease, the surviving Purkinje cells are concentrated in lobules IX and X of the posterior lobe vermis. Purkinje cell degeneration is accompanied by the ectopic expression of tyrosine hydroxylase and the small heat shock protein HSP25, both associated preferentially with the surviving cells. The pattern of cell death thus reflects the fundamental compartmentation of the cerebellum into zones and stripes.