Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI

Abstract Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Young Eun Huh, Hyejung Park, Ming Sum Ruby Chiang, Idil Tuncali, Ganqiang Liu, Joseph J. Locascio, Julia Shirvan, Samantha J. Hutten, Melissa S. Rotunno, Catherine Viel, Lamya S. Shihabuddin, Bing Wang, Sergio Pablo Sardi, Clemens R. Scherzer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/55051a3035eb4ec194cc1bc0ad51cd1d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:55051a3035eb4ec194cc1bc0ad51cd1d
record_format	dspace
spelling	oai:doaj.org-article:55051a3035eb4ec194cc1bc0ad51cd1d2021-11-28T12:23:17ZGlucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI10.1038/s41531-021-00241-32373-8057https://doaj.org/article/55051a3035eb4ec194cc1bc0ad51cd1d2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00241-3https://doaj.org/toc/2373-8057Abstract Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.Young Eun HuhHyejung ParkMing Sum Ruby ChiangIdil TuncaliGanqiang LiuJoseph J. LocascioJulia ShirvanSamantha J. HuttenMelissa S. RotunnoCatherine VielLamya S. ShihabuddinBing WangSergio Pablo SardiClemens R. ScherzerNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Young Eun Huh Hyejung Park Ming Sum Ruby Chiang Idil Tuncali Ganqiang Liu Joseph J. Locascio Julia Shirvan Samantha J. Hutten Melissa S. Rotunno Catherine Viel Lamya S. Shihabuddin Bing Wang Sergio Pablo Sardi Clemens R. Scherzer Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
description	Abstract Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.
format	article
author	Young Eun Huh Hyejung Park Ming Sum Ruby Chiang Idil Tuncali Ganqiang Liu Joseph J. Locascio Julia Shirvan Samantha J. Hutten Melissa S. Rotunno Catherine Viel Lamya S. Shihabuddin Bing Wang Sergio Pablo Sardi Clemens R. Scherzer
author_facet	Young Eun Huh Hyejung Park Ming Sum Ruby Chiang Idil Tuncali Ganqiang Liu Joseph J. Locascio Julia Shirvan Samantha J. Hutten Melissa S. Rotunno Catherine Viel Lamya S. Shihabuddin Bing Wang Sergio Pablo Sardi Clemens R. Scherzer
author_sort	Young Eun Huh
title	Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title_short	Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title_full	Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title_fullStr	Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title_full_unstemmed	Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title_sort	glucosylceramide in cerebrospinal fluid of patients with gba-associated and idiopathic parkinson’s disease enrolled in ppmi
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/55051a3035eb4ec194cc1bc0ad51cd1d
work_keys_str_mv	AT youngeunhuh glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT hyejungpark glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT mingsumrubychiang glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT idiltuncali glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT ganqiangliu glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT josephjlocascio glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT juliashirvan glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT samanthajhutten glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT melissasrotunno glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT catherineviel glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT lamyasshihabuddin glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT bingwang glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT sergiopablosardi glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi AT clemensrscherzer glucosylceramideincerebrospinalfluidofpatientswithgbaassociatedandidiopathicparkinsonsdiseaseenrolledinppmi
_version_	1718408013141770240

Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI

Ejemplares similares