Highly-sensitive simultaneous quantitation of glucosylsphingosine and galactosylsphingosine in human cerebrospinal fluid by liquid chromatography/tandem mass spectrometry

Matsumoto, Shimpei; Sato, Sho; Otake, Kentaro; Kosugi, Yukio

doi:10.1016/j.jpba.2022.114852

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…administration (Fig 4C and S3C Fig). In this study, we were able to detect GlcSph in a small volume of CSF using a highly sensitive quantitation method established for human CSF samples [62]. In summary AAV5-delivered GBA1 , independently of the expression cassette used (AAV5-CBh- GBA1 or AAV5-EFS- GBA1 ), increases GCase activity and reduces GlcSph accumulation in the brain of 4L/PS-NA mice.…”

Section: Resultsmentioning

confidence: 99%

“…For quantitation of endogenous GlcSph in iPS-DA cells, the lipid fractions were extracted by adding an ethanol and isopropanol (1:1) mixture to cells under ice-cold conditions. For quantitation of endogenous GlcSph in mouse tissues or CSF was performed using an ultra-sensitive method previously described [62], also allowing the analysis of mouse CSF. Briefly, tissue samples were homogenized in methanol to prepare 20% (w/v) homogenates for cortex and liver, and 10% (w/v) homogenates for cerebellum, hippocampus, and striatum under ice-cold conditions.…”

Section: Methodsmentioning

confidence: 99%

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AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Okai,

Sato,

Deshpande

et al. 2024

Preprint

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Biallelic mutations in theglucosylceramidase beta 1(GBA1) gene are the underlying genetic cause of Gaucher’s disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently,GBA1mutations have been identified as the most prevalent genetic risk factor for Parkinson’s disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the α-synuclein pathology is more prominent, and recent data suggest a link between α-synucleinopathies andGBA1mutations. Here, we explored the effect ofGBA1gene supplementation on the GD phenotypes and α-synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the samein vitroandin vivo. GBA1overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate thatGBA1overexpression can dissolve phospho-α-synuclein aggregation induced by the addition of α-synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of β-Glucocerebrosidase (GCase) on α-synuclein accumulation.In vivo, we show that GCase inhibition can induce insoluble high-molecular-weight α-synuclein aggregation and that delivery ofGBA1achieves robust reduction of the α-synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes α-synuclein aggregates which are the hallmark for PD and α-synucleinopathies. AAV delivery ofGBA1is a powerful approach to restore glucocerebrosidase function and to resolve misfolded α-synuclein protein, with applications for GD and PD.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Okai,

Sato,

Deshpande

et al. 2024

Preprint

Self Cite

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“…Considering the molecular advances in the diagnosis of typical and atypical KD, more costly and invasive procedures are often unnecessary diagnostically. Tools such as CSF protein quantification, while a nonspecific finding, can be used for prognosis and as an indicator of treatment success [48]. Additionally, nerve conduction studies and advanced imaging such as MRI or CT may help localize specific areas of demyelination and atrophy throughout the cortical white matter and peripherally to provide information about symptom manifestations and prognosis [37].…”

Section: Evaluation Of Krabbementioning

confidence: 99%

Krabbe Disease–To Add or Not to Newborn Screening?

Kanungo,

Vergano,

Clark

et al. 2024

OBM Genet

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Krabbe disease (KD), a severe neurodegenerative disorder, has been controversial in the space of newborn screening (NBS) in the United States. Families continue to advocate for the addition of KD to the Recommended Uniform Screening Panel (RUSP) after being declined for the second time in February 2023. Even with significant progress in KD screening tests, uncertainty about the phenotypic presentations, and effectiveness of hematopoietic stem cell transplant (HSCT) seems to have impeded the addition of this condition to the RUSP. Potential in-utero onset of symptoms in early infantile onset Krabbe disease (EIKD) raise questions on the ‘pre-symptomatic’ requirement of NBS. This paper reviews the current knowledge of KD, including accepted and investigational treatments to help further the discussion for adding KD on NBS panels.

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The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson’s Disease: a New Genetic State of the Art

dos Santos,

Mano,

da Cunha Barreto-Vianna

et al. 2024

Mol Neurobiol

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Highly-sensitive simultaneous quantitation of glucosylsphingosine and galactosylsphingosine in human cerebrospinal fluid by liquid chromatography/tandem mass spectrometry

Cited by 5 publications

References 34 publications

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

Krabbe Disease–To Add or Not to Newborn Screening?

The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson’s Disease: a New Genetic State of the Art

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