Research focus
The art of protein tailoring
In the vast universe of cell biology, there exists a hidden layer of molecular complexity that goes beyond the mere sequence of genetic information. Welcome to the captivating realm of post-translational modifications (PTMs), where proteins undergo a series of remarkable alterations that significantly impact their structure, function, and destiny within the cell. Not suprisingly, abundant evidence points towards PTMs being hubs and drivers of immune and glial cell (dys)function in health and disease. Specifically, our findings highlight the importance of protein tagging with ubiquitin and fatty acids, also called ubiquitination and protein acetylation, in fine-tuning neuroinflammation, remyelination, and immune cell function. For example, we found that faulty ubiquitination of ABC efflux transporters results in an intracellular lipid traffic jam and partially underlies perturbed macrophage and microglia function in the damaged brain. Similar, we uncovered that modulation of protein acetylation holds tremendous therapeutic potential to drive innate and adaptive immune cells towards a disease-resolving phenotype in autoimmune and brain disorders. Currently, we continue to decode the sophisticated language of protein tagging, and, in doing so, we hope to gain increased insight into PTM function in health and disease as well as identify novel targets for therapeutic interventions.
Butter up your nerves
Failure of remyelination, the formation of new myelin sheaths surrounding axons, is considered to underlie the progressive nature of demyelinating disorders such as multiple sclerosis (MS). To date, however, there are no therapeutic agents that can effectively induce or enhance myelin regeneration in these disorders. Emerging evidence indicates that subtle changes in cellular and tissular lipid levels and metabolism have a major impact on the formation of myelin-forming oligodendrocytes and remyelination. In support of this notion, our exciting preliminary data indicate that imbalances in the level and metabolism of glycerolipids, a major lipid component of myelin membranes, are closely associated with failure of remyelination. Therefore, we hypothesize that glycerolipid synthesis, uptake, and turnover are essential for oligodendrocyte formation and remyelination. By using innovative state-of-the-art lipidomic and transcriptomic approaches, preclinical animal models, and postmortem human brain tissue, we here aim to identify glycerolipid metabolism as novel therapeutic target to promote remyelination, and to provide detailed insight into lipid function in progressive demyelinating disorders such as MS. All in all, findings from this study will lead to the identification of novel clinically-relevant strategies to promote brain repair in neurological disorders.
Inflammasome follies
Autoinflammatory diseases (AIDs) are a group of rare monogenetic disorders characterized by recurrent episodes of fever and systemic inflammation. A major pathological hallmark of AIDs is excessive assembly and activation of inflammasomes, often the result of gain-of-function mutations in genes encoding core inflammasome components, including pyrin and cryopyrin. Recent advances in lipidomics have unveiled that dysregulated metabolism of lipids such as cholesterol and fatty acids, especially in innate immune cells, exerts complex effects on inflammasome activation and the pathogenesis of AIDs. We aim to unravel the impact of lipids and their metabolism on inflammasome activation and the disease pathogenesis of the most common AIDs, including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), and hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS). We postulate that lipids hold diagnostic value in AID and that dietary and pharmacological intervention studies could represent a promising approach to attenuate inflammasome activation and AID disease progression.
Lipid lunacy in CMT1A
Charcot-Marie-Tooth disease type 1A (CMT1A) is a prevalent inherited disorder of the peripheral nervous system, affecting approximately 1 in 2500 individuals. This condition arises from a duplication of the PMP22 gene, leading to peripheral nerve damage. CMT1A patients grapple with profound muscle weakness, atrophy, sensory loss, and chronic pain in the extremities, significantly impacting their quality of life. Unfortunately, no effective treatments for CMT1A currently exist. The root cause of the disease lies in the malfunctioning of Schwann cells (SCs), which are unable to properly ensheath nerves, resulting in dysfunctional myelination. While the underlying mechanism remains elusive, it is becoming evident that the proper balance of phospholipids and cholesterol, vital components of SC membranes, is disrupted in CMT1A. In this study, we aim to investigate the hypothesis that impaired phospholipid and cholesterol metabolism in Schwann cells contributes to the myelination deficits observed in CMT1A. Through a series of experiments utilizing both mouse SCs and human-derived SCs, as well as innovative lipidomic approaches, we seek to uncover disturbances in the phospholipid and cholesterol homeostasis, explore the impact of interventions targeting these pathways on SC myelination, and validate our findings using a CMT1A mouse model. By shedding light on the intricate molecular mechanisms at play, our research aims to provide valuable insights and potential therapeutic targets for the development of much-needed CMT1A treatments.
Size does not matter
Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Our findings indicate that extracellular vesicles (EVs), nano-sized biogenic particles, secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance dictate the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders. Currently, we are investigating the impact of other lipids on the inflammatory and regenerative properties of EVs released by a variety of immune and glial cells.
Brain bubble trouble
Macrophages and microglia are increasingly being acknowledged to act both as drivers and suppressors of disease progression in neurodegenerative disorders. Dynamic fine-tuning of their physiology is anticipated to underlie this dual function. Together with Prof. dr. Jerome Hendriks, we demonstrated that lipids are key regulators of the benign and harmful effector functions of phagocytes in the brain. Specifically, we found that after CNS insults, macrophages and microglia initially adopt an inflammatory, disease-promoting phenotype that is characterized by elevated expression of endocytic receptors that drive demyelination and neurodegeneration. In time, however, uptake and intracellular processing of myelin generates protective lipid metabolites capable of inducing a disease-resolving phenotype. Our latest findings indicate that the disease-resolving phenotype that myelin-phagocytosing foam cells display in brain lesions is only transient. Persistent accumulation of myelin within phagocytes eventually blunts their protective features and promotes an inflammatory transcriptional profile that limits CNS repair. Disturbances in the intracellular processing and efflux of myelin-derived lipids underpin the induction of this harmful phenotype. Despite identifying some of the factors driving the triphasic phenotype exhibited by phagocytes in the damaged and inflamed brain, the Hendriks and Bogie labs remain dedicated to unraveling the metabolic and molecular mechanisms underlying phagocyte plasticity in demyelinating disorders, applying different research methodologies and perspectives. Specifically, the Bogie lab focuses on investigating the impact of single nucleotide polymorphisms and post-transcriptional modifications on the physiology of macrophages and microglia, including those with a foamy appearance. Additionally, we aim to evaluate how stearoyl-CoA desaturase isoforms influence the metabolic and inflammatory phenotype of foamy phagocytes. By comprehensively understanding the metabolic and molecular blueprint governing phagocyte plasticity, the Hendriks and Bogie labs hope to advance our knowledge of neurodegenerative disorders and identify potential therapeutic targets to modulate phagocyte physiology in the brain.
Location
Hasselt University
Biomedical Research Institute
Department of Immunology and Infection
Agoralaan Building C
3590 Diepenbeek
Belgium