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A 4-month-old female mixed-breed cat showed gait disturbance and eventual dysstasia with intention tremor and died at 14 months of age. Postmortem histological analysis revealed degeneration of neuronal cells, alveolar epithelial cells, hepatocytes, and renal tubular epithelial cells. Infiltration of macrophages was observed in the nervous system and visceral organs. The cytoplasm of neuronal cells was filled with Luxol fast blue (LFB)-negative and periodic acid-Schiff (PAS)-negative granules, and the cytoplasm of macrophages was LFB-positive and PAS-negative. Ultrastructurally, concentric deposits were observed in the brain and visceral organs. Genetic and biochemical analysis revealed a nonsense mutation (c.1017G>A) in the SMPD1 gene, a decrease of SMPD1 mRNA expression, and reduced acid sphingomyelinase immunoreactivity. Therefore, this cat was diagnosed as having Niemann-Pick disease with a mutation in the SMPD1 gene, a syndrome analogous to human Niemann-Pick disease type A.

Recent studies have shown that many kinds of stem cells are beneficial for patients suffering with neurodegenerative diseases. We investigated the effects of neural stem cell (NSC), Maudsley hippocampal clone 36 (MHP36) in the Niemann-Pick disease type C (NP-C) model mice. Herein, we demonstrate that MHP36 transplantation improves the neuropathological features without acute immune response and promotes neuronal networks with functional synaptic transmission. The number of surviving Purkinje neurons substantially increased in MHP36 transplanted NP-C mice compared with sham-transplanted NP-C mice. MHP36 significantly reduced both of astrocytic and microglial activations. We also found that these surviving Purkinje neurons have normal functional synapses with parallel fibers that have normal glutamate release probability in MHP36 transplanted NP-C mice. Furthermore, real-time PCR analysis revealed up-regulation of genes involved in both excitatory and inhibitory neurotransmission encoding subunits of the ionotropic glutamate receptors GluR2, 3 and GABAA receptor beta2. These findings suggest that NSC, MHP36 transplantation may have therapeutic effects in the treatment of NP-C and other neurodegenerative diseases.

Niemann-Pick type C (NP-C) disease is a devastating developmental disorder with progressive and fatal neurodegeneration. We have used a mouse model of Niemann-Pick type C (NP-C) disease to evaluate the effects of direct intracerebral transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) on the progression of neurological disease in this order. Here, we show that hUCB-MSCs transplantation into NP-C mice prevents the loss of Purkinje neurons and inhibits cerebellar apoptotic cell death. Interestingly, these effects were associated with the modulation of inflammatory responses, as evidenced by increased anti-inflammatory cytokine IL-10, and reduced abnormal astrocytic activation. Furthermore, our results show that the hUCB-MSCs transplantation reduced the cholesterol accumulation level in neurons in NP-C mice compared with sham-transplanted animals. This study provides the first evidence that hUCB-MSCs can improve neurological symptoms in NP-C disease, suggesting it as a potential therapeutic agent against neurodegenerative diseases.

Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurologic dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurologic and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by postrotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 wk. CNS and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurologic and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model.

A 5-month-old Hereford calf with neurologic disease was euthanatized, and a necropsy was done. No gross lesions were seen in the brain. Microscopically, neurons throughout the brain and spinal cord had distended, foamy vacuolated cytoplasm. Ultrastructure showed clear vacuoles filling the neuronal cytoplasm. A lysosomal storage disease was suspected. Sphingomyelinase deficiency was confirmed by biochemical analysis of liver and brain.

After transplantation, adult bone marrow-derived mesenchymal stem cells (BM-MSCs) may undergo transdifferentiation and/or cell fusion in response to new environments. However, the mechanism(s) that govern these cell fate switches remain unknown. Here we demonstrate that the pathology associated with murine Niemann-Pick disease type C (NP-C) cerebellum augments the ability of BM-MSCs to fuse with Purkinje neurons. The results suggest that the degenerative microenvironment of Purkinje neurons in the NP-C cerebellum modulates the cell fate switch of BM-MSCs via cell fusion.

Niemann-Pick type C (NPC) disease is a lysosomal disorder commonly caused by a recessive mutation in NPC1, which encodes an integral membrane protein with regions of homology to the morphogen receptor, Patched, and to 3-hydroxy-3-methylglutaryl coenzyme A reductase. Neurons in NPC disease exhibit extensive storage of free cholesterol and glycosphingolipids (GSLs), including GM2 and GM3 gangliosides. Most studies have viewed cholesterol storage as primary, with NPC1 functioning as a retroendocytic transporter for regulation of cholesterol homeostasis. Here, we analyze the effects of genetically depriving NPC neurons of complex gangliosides by creating mice doubly deficient in both NPC1 and the GSL synthetic enzyme, GM2/GD2 synthase (GalNAcT). Ganglioside and cholesterol expression in neurons of NPC1(-/-)/GalNAcT(+/+), NPC1(-/-)/GalNAcT(-/-), NPC1(+/+)/GalNAcT(-/-), and WT mice was examined in situ by immunocytochemical and histochemical methods. Neurons in double-deficient mice lacked intraneuronal GM2 accumulation as expected, but remarkably also exhibited absence or dramatic reduction in free cholesterol. Neurons storing cholesterol consistently showed GM3 accumulation but some GM3-positive neurons lacked cholesterol storage. These findings provide a compelling argument that cholesterol sequestration in NPC1-deficient neurons is ganglioside dependent and suggest that the function of NPC1 in these cells may be more closely linked to homeostatic control of GSLs than cholesterol.

Complementation studies were performed to determine if the gene responsible for the major form of human Niemann-Pick type C disease (NPC) and a feline model of NPC are orthologous. Cell fusions between human NPC and feline NPC fibroblasts were conducted to assess whether the multinucleated heterokaryons that were formed showed a reversal of the NPC phenotype. Cultured fibroblasts from NPC-affected humans and NPC-affected cats were hybridized and then analyzed for complementation by challenging the cells with low-density lipoprotein (LDL) and subsequently staining with the fluorescent antibiotic filipin to visualize any abnormal accumulation of unesterified cholesterol. All of the multinucleated cells formed from these fusions retained the NPC staining phenotype, indicating an absence of complementation and suggesting that the underlying defect in the major form of human NPC and this feline model of NPC involve orthologous genes., (Copyright 1999 Academic Press.)

Seven Domestic shorthair cats with a lysosomal storage disorder analogous to human Niemann-Pick disease type C, from a breeding colony were studied to characterize the neurological manifestations of this disorder. Affected cats were identified by means of liver biopsies at 4 to 6 weeks of age. Neurological examinations were performed at 2 week intervals from the onset of clinical signs. All cats displayed signs referrable to the cerebellum, with a subtle intention tremor noticed initially at 8 to 12 weeks of age; the disease was rapidly progressive. The tremor became more pronounced, menace response was lost, and severe dysmetria and ataxia developed. Three cats also had signs referrable to other areas of the central nervous system. Cats died or were euthanized between 12 and 43 weeks of age. Pathological findings included accumulation of substrate within neurons throughout the central nervous system, and axonal spheroid formation. The clinical and pathological findings in these cats are comparable to those in the human form of the disease.

Pathological and biochemical studies were performed on a 9-month-old boxer dog with progressive neurological abnormality. Histological examination revealed marked neuronal storage throughout the central nervous system and histiocytic storage in the reticuloendothelial system. Ultrastructurally, the neuronal storage consisted of accumulation of concentric membranous inclusions and clusters of dense bodies. The biochemically unesterified cholesterol content was high in the liver and spleen. The brain showed increased levels of lactosylceramide and two gangliosides, GM3 and GM2. These findings indicate that this dog was affected with a heterogeneous lipid storage disease similar to the human Niemann-Pick type C disease.

Foamy cells in non-nervous tissues from a female Siamese cat with sphingomyelinosis were examined by lectin histochemistry. Many foamy cells, so-called Niemann-Pick cells, were found in the non-nervous tissues, such as liver, spleen, lung, kidney, adrenal gland, lymph node and tonsil. These cells were positive for Concanavalia ensiformis agglutinin, Ricinus communis agglutinin-I and wheat germ agglutinin. Storage materials in the foamy cells were different from those in affected cells of the nervous tissues. This study suggests that lectin histochemistry might be helpful in the diagnosis of sphingomyelinosis.

A 5-month-old minature Poodle dog had widespread cytoplasmic vacuolation of neurons in the central nervous system and foamy macrophages in the lung, spleen, renal lymph node, liver, adrenal gland and intestine. Concentric membranous cytoplasmic inclusions were seen in the neurons of the central nervous system by electron microscopy. There was no sphingomyelinase in the brain tissue. Sphingomyelin and cholesterol were increased in brain, kidney and liver. A diagnosis of Niemann-Pick Disease was based on absence of sphingomyelinase activity, as well as on histologic, histochemical and chemical findings.

Two related cats, aged 5 months and 7 months, and 1 unrelated cat, aged 4 months, presented with signs of a progressive neuromuscular disease. Detailed electrophysiological studies suggested a primary demyelinating polyneuropathy, which was confirmed by muscle and nerve biopsies and on necropsy examination. Light and electron microscopic findings indicated a lysosomal storage disease, which was diagnosed as sphingomyelinase deficiency (Niemann-Pick disease) by enzyme analysis and lipid fractionation, although significant biochemical differences existed between the 2 related cats and the third cat. Several lines of evidence suggest that these 2 related cats were affected with a variant of type A Niemann-Pick disease, whereas cat 3 represented classic Niemann-Pick disease type A.

A 7-month-old Balinese cat with progressive neurological dysfunction had histopathological lesions of brain, liver, kidney, spleen, and lung consistent with a lysosomal storage disease. Ultrastructural examination revealed lysosomal hypertrophy with membranous inclusions. Hepatic sphingomyelin and cholesterol were elevated 10 times normal, and total phospholipids were increased 3.6 fold. Sphingomyelinase activity measured with 14C labeled sphingomyelin at pH 5.0 was virtually absent in brain and liver. Other lysosomal hydrolase activities were normal or elevated. Clinical, morphological, and biochemical findings suggest that this cat had sphingomyelin lipidosis similar to human Niemann-Pick disease type A, and that feline sphingomyelin lipidosis provides another model of human lysosomal storage disease.