Substrate Compositional Variation with Tissue/Region and Gba1 Mutations in Mouse Models–Implications for Gaucher Disease

Sun, Ying; Zhang, Wujuan; Xu, You-Hai; Quinn, Brian; Dasgupta, Nupur; Liou, Benjamin; Setchell, Kenneth D.R.; Grabowski, Gregory A.

doi:10.1371/journal.pone.0057560

Cited by 42 publications

(47 citation statements)

References 30 publications

(61 reference statements)

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“…The levels of GlcSph have been shown to be increased in human GD brains and GD mouse models . GlcSph was unaffected in the putamen and cerebellum of PD+GBA and sporadic PD brains, when compared with control.…”

Section: Resultsmentioning

confidence: 96%

“…The mechanism by which loss of GCase activity affects the ALP is unclear. The accumulation of GlcCer or glucosylsphingosine (GlcSph; deacetylated GlcCer) could contribute to lysosomal dysfunction and toxicity, and so to the pathogenesis of PD in GBA1 mutation carriers . However, although PD+GBA brains have significant loss of GCase activity, the residual function of the enzyme may be sufficient to prevent substrate accumulation.…”

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confidence: 99%

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No evidence for substrate accumulation in Parkinson brains with GBA mutations

Gegg¹,

Sweet²,

Wang³

et al. 2015

Movement Disorders

129

108

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BackgroundTo establish whether Parkinson’s disease (PD) brains previously described to have decreased glucocerebrosidase activity exhibit accumulation of the lysosomal enzyme’s substrate, glucosylceramide, or other changes in lipid composition.MethodsLipidomic analyses and cholesterol measurements were performed on the putamen (n = 5-7) and cerebellum (n = 7-14) of controls, Parkinson’s disease brains with heterozygote GBA1 mutations (PD+GBA), or sporadic PD.ResultsTotal glucosylceramide levels were unchanged in both PD+GBA and sporadic PD brains when compared with controls. No changes in glucosylsphingosine (deacetylated glucosylceramide), sphingomyelin, gangliosides (GM2, GM3), or total cholesterol were observed in either putamen or cerebellum.ConclusionsThis study did not demonstrate glucocerebrosidase substrate accumulation in PD brains with heterozygote GBA1 mutations in areas of the brain with low α-synuclein pathology.

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Section: Resultsmentioning

confidence: 96%

mentioning

confidence: 99%

No evidence for substrate accumulation in Parkinson brains with GBA mutations

Gegg¹,

Sweet²,

Wang³

et al. 2015

Movement Disorders

129

108

View full text Add to dashboard Cite

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“…Frozen cell pellets were shipped on dry ice to Cincinnati Children’s Hospital for glucosylsphingosine analysis. Lipid extraction and LC–MS/MS analysis of glucosylsphingosine accumulation was performed as previously described (Sun et al, 2012, 2013). All quantitative glucosylsphingosine data was normalized to total protein detected in the cell lysate.…”

Section: Methodsmentioning

confidence: 99%

A peptide-linked recombinant glucocerebrosidase for targeted neuronal delivery: Design, production, and assessment

Gramlich

Westbroek

Feldman

et al. 2016

Journal of Biotechnology

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Although recombinant glucocerebrosidase (GCase) is the standard therapy for the inherited lysosomal storage disease Gaucher’s disease (GD), enzyme replacement is not effective when the central nervous system is affected. We created a series of recombinant genes/proteins where GCase was linked to different membrane binding peptides including the Tat peptide, the rabies glycoprotein derived peptide (RDP), the binding domain from tetanus toxin (TTC), and a tetanus like peptide (Tet1). The majority of these proteins were well-expressed in a mammalian producer cell line (HEK 293F). Purified recombinant Tat-GCase and RDP-GCase showed similar GCase protein delivery to a neuronal cell line that genetically lacks the functional enzyme, and greater delivery than control GCase, Cerezyme (Genzyme). This initial result was unexpected based on observations of superior protein delivery to neurons with RDP as a vector. A recombinant protein where a fragment of the flexible hinge region from IgA (IgAh) was introduced between RDP and GCase showed substantially enhanced GCase neuronal delivery (2.5 times over Tat-GCase), suggesting that the original construct resulted in interference with the capacity of RDP to bind neuronal membranes. Extended treatment of these knockout neuronal cells with either Tat-GCase or RDP-IgAh-GCase resulted in an >90% reduction in the lipid substrate glucosylsphingosine, approaching normal levels. Further in vivo studies of RDP-IgAh-GCase as well as Tat-GCase are warranted to assess their potential as treatments for neuronopathic forms of GD. These peptide vectors are especially attractive as they have the potential to carry a protein across the blood–brain barrier, avoiding invasive direct brain delivery.

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“…Intensities of the secondary ions relating to psychosine (m/z 462-N264, 282, 444) and the ISTD (m/z 490-N 292, 294, 310, 472) were summed up, and the response ratios were calculated, which were then compared to calibration curves derived from addition of psychosine standard (0-8 nmol) and ISTD (1 nmol) to brain tissue of wild type mice before extraction. It has to be mentioned, that this method cannot distinguish psychosine from its epimer glucosylsphingosine, which is, however, of very low abundance in tissues unless β-glucocerebrosidase or saposin C is deficient (Sun et al, 2013).…”

Section: Psychosine Quantificationmentioning

confidence: 99%