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

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 cerebrospi...

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Autores principales: Huh, Young Eun, Park, Hyejung, Chiang, Ming Sum Ruby, Tuncali, Idil, Liu, Ganqiang, Locascio, Joseph J., Shirvan, Julia, Hutten, Samantha J., Rotunno, Melissa S., Viel, Catherine, Shihabuddin, Lamya S., Wang, Bing, Sardi, Sergio Pablo, Scherzer, Clemens R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608962/
https://www.ncbi.nlm.nih.gov/pubmed/34811369
http://dx.doi.org/10.1038/s41531-021-00241-3
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author Huh, Young Eun
Park, Hyejung
Chiang, Ming Sum Ruby
Tuncali, Idil
Liu, Ganqiang
Locascio, Joseph J.
Shirvan, Julia
Hutten, Samantha J.
Rotunno, Melissa S.
Viel, Catherine
Shihabuddin, Lamya S.
Wang, Bing
Sardi, Sergio Pablo
Scherzer, Clemens R.
author_facet Huh, Young Eun
Park, Hyejung
Chiang, Ming Sum Ruby
Tuncali, Idil
Liu, Ganqiang
Locascio, Joseph J.
Shirvan, Julia
Hutten, Samantha J.
Rotunno, Melissa S.
Viel, Catherine
Shihabuddin, Lamya S.
Wang, Bing
Sardi, Sergio Pablo
Scherzer, Clemens R.
author_sort Huh, Young Eun
collection PubMed
description 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.
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spelling pubmed-86089622021-12-01 Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI Huh, Young Eun Park, Hyejung Chiang, Ming Sum Ruby Tuncali, Idil Liu, Ganqiang Locascio, Joseph J. Shirvan, Julia Hutten, Samantha J. Rotunno, Melissa S. Viel, Catherine Shihabuddin, Lamya S. Wang, Bing Sardi, Sergio Pablo Scherzer, Clemens R. NPJ Parkinsons Dis Article 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. Nature Publishing Group UK 2021-11-22 /pmc/articles/PMC8608962/ /pubmed/34811369 http://dx.doi.org/10.1038/s41531-021-00241-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Huh, Young Eun
Park, Hyejung
Chiang, Ming Sum Ruby
Tuncali, Idil
Liu, Ganqiang
Locascio, Joseph J.
Shirvan, Julia
Hutten, Samantha J.
Rotunno, Melissa S.
Viel, Catherine
Shihabuddin, Lamya S.
Wang, Bing
Sardi, Sergio Pablo
Scherzer, Clemens R.
Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608962/
https://www.ncbi.nlm.nih.gov/pubmed/34811369
http://dx.doi.org/10.1038/s41531-021-00241-3
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