Regulation of Oligodendrocyte Differentiation and Myelination by Nuclear Receptors: Role in Neurodegenerative Disorders

Sandoval-Hernández, Adrián G.; Contreras, María José; Jaramillo, Joseph; Arboleda, Gonzálo

doi:10.1007/978-3-319-40764-7_14

Cited by 5 publications

(4 citation statements)

References 153 publications

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“…Furthermore, polyunsaturated fatty acid levels in the blood are correlated with white-matter integrity in frontal regions of the SZ brain 78 , whereas increased LDL levels are associated with white-matter alterations 79 , and white matter, as well as myelin abnormalities in the PFC contribute to cognitive deficits in SZ 76 . Myelin lipids are produced by oligodendrocytes (OLs) and LXRβ-knockout mice show a hypomyelination phenotype, because cholesterol deficiency inhibits OL differentiation and myelination 80,81 . During brain development, LXRβ is also involved in the formation of OL precursor cells 82 and exerts transcriptional control over myelin-related genes 83 .…”

Section: Discussionmentioning

confidence: 99%

Key role for lipids in cognitive symptoms of schizophrenia

Maas

Martens²,

Priovoulos

et al. 2020

Transl Psychiatry

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Schizophrenia (SZ) is a psychiatric disorder with a convoluted etiology that includes cognitive symptoms, which arise from among others a dysfunctional dorsolateral prefrontal cortex (dlPFC). In our search for the molecular underpinnings of the cognitive deficits in SZ, we here performed RNA sequencing of gray matter from the dlPFC of SZ patients and controls. We found that the differentially expressed RNAs were enriched for mRNAs involved in the Liver X Receptor/Retinoid X Receptor (LXR/RXR) lipid metabolism pathway. Components of the LXR/RXR pathway were upregulated in gray matter but not in white matter of SZ dlPFC. Intriguingly, an analysis for shared genetic etiology, using two SZ genome-wide association studies (GWASs) and GWAS data for 514 metabolites, revealed genetic overlap between SZ and acylcarnitines, VLDL lipids, and fatty acid metabolites, which are all linked to the LXR/RXR signaling pathway. Furthermore, analysis of structural T1-weighted magnetic resonance imaging in combination with cognitive behavioral data showed that the lipid content of dlPFC gray matter is lower in SZ patients than in controls and correlates with a tendency towards reduced accuracy in the dlPFC-dependent task-switching test. We conclude that aberrations in LXR/RXR-regulated lipid metabolism lead to a decreased lipid content in SZ dlPFC that correlates with reduced cognitive performance.

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Section: Discussionmentioning

confidence: 99%

Key role for lipids in cognitive symptoms of schizophrenia

Maas

Martens²,

Priovoulos

et al. 2020

Transl Psychiatry

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“…Several nuclear receptors regulate oligodendrocyte differentiation and myelination [ 39 ]. LXRs differentially affect the mRNA amounts of myelin genes in myelin-rich tissues, such as spinal cord, corpus callosum, optic nerve and cerebellum [ 40 ].…”

Section: Lxrs and Oligodendrocytesmentioning

confidence: 99%

Liver X Receptor Regulation of Glial Cell Functions in the CNS

Song

Warner

et al. 2022

Biomedicines

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In this review, we discuss the role of liver X receptors (LXRs) in glial cells (microglia, oligodendrocytes and astrocytes) in the central nervous system (CNS). LXRs are oxysterol-activated nuclear receptors that, in adults, regulate genes involved in cholesterol homeostasis, the modulation of inflammatory responses and glutamate homeostasis. The study of LXR knockout mice has revealed that LXRβ plays a key role in maintaining the health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord and retinal ganglion cells in the eye. In the peripheral nervous system (PNS), LXRβ is responsible for the health of the spiral ganglion neurons (SGNs) in the cochlea. In addition, LXRs are essential for the homeostasis of the cerebrospinal fluid (CSF), and in LXRαβ−/− mice, the lateral ventricles are empty and lined with lipid-laden cells. As LXRαβ−/− mice age, lipid vacuoles accumulate in astrocytes surrounding blood vessels. By seven months of age, motor coordination becomes impaired, and there is a loss of motor neurons in the spinal cord of LXRβ−/− mice. During development, migration of neurons in the cortex and cerebellum is retarded in LXRβ−/− mice. Since LXRs are not expressed in dopaminergic or motor neurons in adult mice, the neuroprotective effects of LXRs appear to come from LXRs in glial cells where they are expressed. However, despite the numerous neurological deficits in LXR−/− rodents, multiple sclerosis has the clear distinction of being the only human neurodegenerative disease in which defective LXR signaling has been identified. In this review, we summarize the regulation and functions of LXRs in glial cells and analyze how targeting LXRs in glial cells might, in the future, be used to treat neurodegenerative diseases and, perhaps, disorders caused by aberrant neuronal migration during development.

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“…Myelin is fundamentally a lipid structure whose main components are cholesterol (40%) and glycosphingolipids (20%). While cholesterol allows the pods to be compacted, glycosphingolipids are necessary to form lipid rafts, facilitating communication with the cell and the extracellular matrix through its glycosylated residues [49], [50]. The synthesis of these compounds occurs in OLs and it is regulated by nuclear-receptor transcription factors.…”

Section: Remyelination Enhancers For the Treat-ment Of Msmentioning

confidence: 99%

“…Both LXR and PPAR are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. When LXR and PPAR are bound to the ligand, they form heterodimers with RXR and target genes that regulate the maturation of the OLs [50]. Sterol regulatory element (SREBP) is another transcription factor implicated in the synthesis of these compounds [51], whose expression is controlled by the PI3K-AK-T1-mTOR signaling pathway in mammals [52].…”

Section: Remyelination Enhancers For the Treat-ment Of Msmentioning

confidence: 99%

Recent Advances on Immunosuppressive Drugs and Remyelination Enhancers for the Treatment of Multiple Sclerosis

Cadenas-Fernández

Ahumada-Pascual

Andreu

et al. 2021

CPD

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: Mammalian nervous systems depend crucially on myelin sheaths covering the axons. In the central nervous system, myelin sheaths consist of lipid structures which are generated from the membrane of oligodendrocytes (OL). These sheaths allow fast nerve transmission, protect axons and provide them metabolic support. In response to specific traumas or pathologies, these lipid structures can be destabilized and generate demyelinating lesions. Multiple sclerosis (MS) is an example of a demyelinating disease in which the myelin sheaths surrounding the nerve fibers of the brain and spinal cord are damaged. MS is the leading cause of neurological disability in young adults in many countries, and its incidence has been increasing in recent decades. Related to its etiology, it is known that MS is an autoimmune and inflammatory CNS disease. However, there are no effective treatments for this disease and the immunomodulatory therapies that currently exist have proven limited success since they only delay the progress of the disease. Nowadays, one of the main goals in the MS research is to find treatments which allows the recovery of neurological disabilities due to demyelination. To this end, different approaches, such as modulating intracellular signaling or regulating the lipid metabolism of OLs, are being considered. Here, in addition to immunosuppressive or immunomodulatory drugs that reduce the immune response against myelin sheaths, we review a diverse group of drugs that promotes endogenous remyelination in MS patients and whose use may be interesting as potential therapeutic agents in MS disease. To this end, we compile specific treatments against MS that are currently in the market with remyelination strategies which have entered into human clinical trials for future reparative MS therapies. The method used in this study is a systematic literature review on PubMed, Web of Science and Science Direct databases up to May 31, 2020. To narrow down the search results in databases, more specific keywords, such as, “myelin sheath”, “remyelination”, “demyelination”, “oligodendrocyte” and “lipid synthesis” were used to focus the search. We favoured papers published after January, 2015, but did not exclude earlier seminal papers.

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Regulation of Oligodendrocyte Differentiation and Myelination by Nuclear Receptors: Role in Neurodegenerative Disorders

Cited by 5 publications

References 153 publications

Key role for lipids in cognitive symptoms of schizophrenia

Key role for lipids in cognitive symptoms of schizophrenia

Liver X Receptor Regulation of Glial Cell Functions in the CNS

Recent Advances on Immunosuppressive Drugs and Remyelination Enhancers for the Treatment of Multiple Sclerosis

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