Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach

Caterina Giovagnoni; Muhammad Ali; Lars M T Eijssen; Richard Maes; Kyonghwan Choe; Monique Mulder; Jos Kleinjans; Antonio Del Sol; Enrico Glaab; Diego Mastroeni; Elaine Delvaux; Paul Coleman; Mario Losen; Ehsan Pishva; Pilar Martinez-Martinez; Daniel L A van den Hove

doi:10.1016/j.neurobiolaging.2021.02.001

Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach

Neurobiol Aging. 2021 Jun:102:178-187. doi: 10.1016/j.neurobiolaging.2021.02.001. Epub 2021 Feb 7.

Authors

Caterina Giovagnoni¹, Muhammad Ali², Lars M T Eijssen³, Richard Maes³, Kyonghwan Choe⁴, Monique Mulder⁵, Jos Kleinjans⁶, Antonio Del Sol⁷, Enrico Glaab⁸, Diego Mastroeni⁹, Elaine Delvaux⁹, Paul Coleman⁹, Mario Losen⁴, Ehsan Pishva¹⁰, Pilar Martinez-Martinez⁴, Daniel L A van den Hove¹¹

Affiliations

¹ School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. Electronic address: [email protected].
² School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Computational Biology Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; Biomedical Data Science Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
³ School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, the Netherlands.
⁴ School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.
⁵ Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁶ Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
⁷ Computational Biology Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.
⁸ Biomedical Data Science Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
⁹ Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.
¹⁰ School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; University of Exeter Medical School, University of Exeter, Exeter, UK.
¹¹ School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.

PMID: 33773368
DOI: 10.1016/j.neurobiolaging.2021.02.001

Abstract

Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions. The SL pathway has been shown to be affected in several brain-related disorders, including Alzheimer's disease (AD). Recent evidence suggests that epigenetic dysregulation plays an important role in the pathogenesis of AD as well. Here, we use an integrative approach to better understand the relationship between epigenetic and transcriptomic processes in regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of 252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32 healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD patients. Additionally, methylomic analysis of the same subjects revealed parallel hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD. Subsequent gene regulatory network-based analysis identified 3 candidate genes, that is, SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression program from a diseased towards a healthy state. Together, this epigenomic and transcriptomic approach highlights the importance of SL-related genes in AD, and may provide novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways in AD.

Keywords: Alzheimer's disease; Disease network analysis; Epigenetics; Gene regulatory network; Sphingolipids.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Alzheimer Disease / genetics*
Caveolin 1 / genetics
Caveolin 1 / metabolism
Epigenesis, Genetic / genetics*
Female
Gene Expression
Gene Expression Profiling
Gene Regulatory Networks / genetics*
Genetic Association Studies*
Humans
Male
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Methylation
Sphingolipids / genetics*
Sphingolipids / metabolism
Sphingolipids / physiology
Temporal Lobe / metabolism
Transcriptome / genetics

Substances

Adaptor Proteins, Signal Transducing
CAV1 protein, human
Caveolin 1
Membrane Glycoproteins
P-selectin ligand protein
SPHKAP protein, human
Sphingolipids

Grants and funding

U24 NS072026/NS/NINDS NIH HHS/United States