Neuropathology of the acid sphingomyelinase knockout mouse model of Niemann-Pick A disease including structure-function studies associated with cerebellar Purkinje cell degeneration.

Niemann-Pick A (NP-A) is an inherited metabolic (lysosomal storage) disease characterized by neurovisceral accumulation of sphingomyelin due to deficiency of acid sphingomyelinase (ASM). An ASM knockout (ASMKO) mouse model of NP-A is available through targeted disruption of the parent gene. This study presents the pattern and time course of lysosomal pathology and neurodegeneration in the ASMKO mouse nervous system. Cells throughout the nervous system developed the classic foamy appearance associated with lysosomal storage disorders. Despite this, neurons were capable of retrogradely transporting dyes within established brain pathways comparable to control animals. A silver degeneration staining method demonstrated widespread damage in the form of 'classic' impregnation of cells, fibers and synaptic terminals. Of particular interest was the degeneration of Purkinje cells (PC) within the cerebellum, beginning by 7 weeks of age in parasagittal bands and culminating with near complete degeneration of this cell type by 20 weeks. In parallel, ASMKO mice had progressively deteriorating motor performance on two versions of the rotating rod test (accelerating and rocking). ASMKO mice at 5-7 weeks of age performed similarly to controls on both rotating rod tests, but performance sharply deteriorated between 7 and 20 weeks of age. This study further characterized the neuropathology associated with ASM deficiency, and identifies quantitative histological and behavioral endpoints for evaluation of therapeutic intervention in this authentic NP-A mouse model.