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

Abstract

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.

Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 −/− mouse

“…5 G and H), indicating activation of glial cells in the areas of Purkinje cell loss. This neurodegeneration occurred in a band-like distribution similar to that described (21). Although the single dose of CYCLO administered at 7 days of age did not alter the number of pyramidal cells present in the cerebral cortex of these 49-day-old animals ( Fig.…”

Cholesterol-Dependent Kinase Activity Regulates Transmitter Release from Cerebellar Synapses

“…Our results suggest that changes in membrane cholesterol content could lead to alterations in presynaptic kinase signaling as neurons develop in vitro. Changes in cholesterol trafficking or metabolism have been implicated in the pathogenesis of several neurodegenerative conditions, most notably Niemann-Pick C1 disease which is caused by mutations of a gene involved in intracellular cholesterol trafficking; this causes cerebellar neurodegeneration (Sarna et al, 2003). A reduction in axonal cholesterol is observed in sympathetic neurons derived from mice deficient for the Niemann-Pick C1 (NPC1) protein (Karten et al, 2002).…”

Altered vitamin E status in Niemann-Pick type C disease

“…It is interesting to note that common pathological and biochemical hallmarks are shared by NPC disease and defi ciency in the dietary antioxidant vitamin E. First, in both cases, the major site of dysfunction is the central nervous system (CNS), and the major clinical presentation is cerebellar ataxia (23)(24)(25), accompanied by specifi c injury to cerebellar Purkinje neurons ( 26,27 ). Second, axonal spheroids (focal swellings) are frequently observed in both NPC disease ( 28 ) and in vitamin E defi ciency (29)(30)(31).…”