Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease
Abstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more commo...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00517-w |
| _version_ | 1797419889874436096 |
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| author | Cheryl E. G. Leyns Alice Prigent Brenna Beezhold Lihang Yao Nathan G. Hatcher Peining Tao John Kang EunRan Suh Vivianna M. Van Deerlin John Q. Trojanowski Virginia M. Y. Lee Matthew E. Kennedy Matthew J. Fell Michael X. Henderson |
| author_facet | Cheryl E. G. Leyns Alice Prigent Brenna Beezhold Lihang Yao Nathan G. Hatcher Peining Tao John Kang EunRan Suh Vivianna M. Van Deerlin John Q. Trojanowski Virginia M. Y. Lee Matthew E. Kennedy Matthew J. Fell Michael X. Henderson |
| author_sort | Cheryl E. G. Leyns |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia. |
| first_indexed | 2024-03-09T06:54:43Z |
| format | Article |
| id | doaj.art-ffdac8823595475f8729dc4c771b2777 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T06:54:43Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-ffdac8823595475f8729dc4c771b27772023-12-03T10:11:04ZengNature Portfolionpj Parkinson's Disease2373-80572023-05-019111410.1038/s41531-023-00517-wGlucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s diseaseCheryl E. G. Leyns0Alice Prigent1Brenna Beezhold2Lihang Yao3Nathan G. Hatcher4Peining Tao5John Kang6EunRan Suh7Vivianna M. Van Deerlin8John Q. Trojanowski9Virginia M. Y. Lee10Matthew E. Kennedy11Matthew J. Fell12Michael X. Henderson13Merck & Co., Inc.Department of Neurodegenerative Science, Van Andel InstituteDepartment of Neurodegenerative Science, Van Andel InstituteMerck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Merck & Co., Inc.Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaInstitute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaInstitute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaInstitute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of PennsylvaniaMerck & Co., Inc.Merck & Co., Inc.Department of Neurodegenerative Science, Van Andel InstituteAbstract Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia.https://doi.org/10.1038/s41531-023-00517-w |
| spellingShingle | Cheryl E. G. Leyns Alice Prigent Brenna Beezhold Lihang Yao Nathan G. Hatcher Peining Tao John Kang EunRan Suh Vivianna M. Van Deerlin John Q. Trojanowski Virginia M. Y. Lee Matthew E. Kennedy Matthew J. Fell Michael X. Henderson Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease npj Parkinson's Disease |
| title | Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease |
| title_full | Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease |
| title_fullStr | Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease |
| title_full_unstemmed | Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease |
| title_short | Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease |
| title_sort | glucocerebrosidase activity and lipid levels are related to protein pathologies in parkinson s disease |
| url | https://doi.org/10.1038/s41531-023-00517-w |
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