Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3

Schueler, Ulrike; Kolter, Thomas; Kaneski, Christine R.; Blusztajn, J. K.; Herkenham, Miles; Sandhoff, Konrad; Brady, Roscoe O.

doi:10.1016/j.nbd.2003.08.016

Cited by 83 publications

(42 citation statements)

References 44 publications

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“…Similar to GD patients, we also found elevated quantities of the second substrate for GCase; glucosylspingosine in the brain of the K14-lnl/lnl mice (data not shown). Previous studies have revealed that accumulation of glucosylsphingosine results in neuronal toxicity (27,28). Our mouse models have implications in the investigation of pathogenic mechanisms that are involved in the CNS manifestations of type 2 GD.…”

Section: Discussionmentioning

confidence: 87%

Murine models of acute neuronopathic Gaucher disease

Enquist

Bianco

Ooka

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

166

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Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.lysosomal storage disorder ͉ glucocerebrosidase deficiency ͉ neurodegeneration ͉ knockout mice ͉ gene therapy

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Section: Discussionmentioning

confidence: 87%

Murine models of acute neuronopathic Gaucher disease

Enquist

Bianco

Ooka

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

166

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“…Other lipids of potential interest include lyso-sulfatide (lyso-SF) (which accumulates in MLD [49]), glucosylsphingosine (GlcSph) and glucosylceramide (GlcCer) (which accumulate in Gaucher disease [47]), and lactosylsphingosine (LacSph) and lactosylceramide (LacCer), which accumulate in several LSDs (Fig 6A) [78, 117, 118]. Some of these lipids appear to have been only rarely studied for their effects on cell function in vitro (lyso-SF, GluSph, LacSph, LacCer) [119]. In the case of Gaucher disease, the majority of previous in vitro studies appears to have focused on GlcCer, and studies on both GlcCer and GlcSph often have required lipid concentrations severalfold greater than those at which Psy’s effects were observed (e.g., [22, 50, 51, 53, 55, 120–122]).…”

Section: Resultsmentioning

confidence: 99%

“…Although some of the effects of individual toxic sphingolipids that we studied have been observed previously with other cell types (although usually at higher lipid concentrations than we utilized, e.g., [51, 61–75, 93, 95, 119–122, 147–154]), there is no previous indication that all of these forms of damage may ultimately be controlled by a single metabolic parameter or that such a parameter might control lysosomal pH. It is also worth noting that, although multiple mechanisms have been observed to contribute to particular effects of Psy or of other toxic lipids [51, 61–75, 82, 120, 123, 147–150, 152–187], none has demonstrated the ability to correct the multiple dysfunctions prevented by promotion of lysosomal re-acidification.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity

et al. 2016

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Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD.

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“…Accumulation of the substrates, GC and its deacylated form GS, is toxic to neural cells and is thought to play a major role in neurodegeneration [11, 46, 48, 49]. GS can mobilize calcium [49] and the accumulation of GC causes excess calcium efflux from the endoplasmic reticulum [50].…”

Section: Discussionmentioning

confidence: 99%

Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease

et al. 2016

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To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD.

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Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3

Cited by 83 publications

References 44 publications

Murine models of acute neuronopathic Gaucher disease

Murine models of acute neuronopathic Gaucher disease

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity

Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease

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