A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice

Zhou, Ye; Bazick, Hannah; Miles, Joshua; Fethiere, Alexander I.; Salihi, Mohammed Omar Al; Fazio, Sergio; Tavori, Hagai; Notterpek, Lucia

doi:10.1016/j.expneurol.2019.113031

Cited by 33 publications

(25 citation statements)

References 71 publications

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“…Consequently, an increase or alteration in dietary fatty acids was proposed as a potential therapeutic strategy for diseases related to myelin formation. Notably, a few recent studies on mouse models for Pelizaeus-Merzbacher or Charcot-Marie-Tooth diseases have shown improvement in myelination when treated with custom lipid diet [153][154][155][156][157]. The mouse model for Pelizaeus-Merzbacher treated with a ketogenic diet for 10 weeks showed reduced axonal degeneration and normalization of motor functions.…”

Section: Fatty Acid Uptakementioning

confidence: 99%

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

Poitelon

Kopec

Belin

2020

Cells

247

152

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Myelin is critical for the proper function of the nervous system and one of the most complex cell–cell interactions of the body. Myelination allows for the rapid conduction of action potentials along axonal fibers and provides physical and trophic support to neurons. Myelin contains a high content of lipids, and the formation of the myelin sheath requires high levels of fatty acid and lipid synthesis, together with uptake of extracellular fatty acids. Recent studies have further advanced our understanding of the metabolism and functions of myelin fatty acids and lipids. In this review, we present an overview of the basic biology of myelin lipids and recent insights on the regulation of fatty acid metabolism and functions in myelinating cells. In addition, this review may serve to provide a foundation for future research characterizing the role of fatty acids and lipids in myelin biology and metabolic disorders affecting the central and peripheral nervous system.

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Section: Fatty Acid Uptakementioning

confidence: 99%

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

Poitelon

Kopec

Belin

2020

Cells

247

152

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“…Notably, several molecules modulate the activity of these enzymes and are used as real drugs in pathological conditions (38). Recent studies demonstrated that soy phospholipid and high-fat neutral lipidenriched diets improve myelination in CMT1A and CMT1E animal models (30,39). It has also been shown that changes in the circulating lipid profile may be related to the onset, activity, and progression of some important human diseases, including myelin disorders (40)(41)(42).…”

Section: Introductionmentioning

confidence: 99%

“…In spite of these observations, lipid metabolism still remains largely under-explored in CMT neuropathies, including CMT1A (39). In fact, it is vital to identify and characterize lipid species and their changes, biological role, and mutual interaction (43).…”

Section: Introductionmentioning

confidence: 99%

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

et al. 2020

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In Charcot–Marie–Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype–phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

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“…Mutations in the pmp22 gene result in >70% of all cases of Charcot-Marie-Tooth disease (CMTD, prevalence: 1:2500) and related peripheral neuropathies (28,29,35). These closely related disorders are characterized by defective myelin membranes that contain altered cholesterol levels relative to healthy myelin (36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Myelin Protein 22 Preferentially Partitions into Ordered Phase Membrane Domains

Marinko

Kenworthy

et al. 2020

Preprint

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The ordered environment of membrane rafts is thought to exclude many transmembrane proteins. Nevertheless, some multi-pass transmembrane proteins have been proposed to partition into ordered domains. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the tetraspan peripheral myelin protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for partitioning to ordered domains. In contrast, disruption of its unusual first transmembrane helix (TM1) reduced ordered phase preference. Charcot-Marie-Tooth disease-causing mutations that destabilize PMP22 also reduced or eliminated this preference in favor of the disordered phase. These studies demonstrate PMP22’s ordered phase preference derives both from the distinctive properties of TM1 and global structural features associated with its transmembrane domain, providing a first glimpse at the structural factors that promote raft partitioning for multi-pass proteins.Significance StatementThe preferential partitioning of single span membrane proteins for the ordered phase of ordered/disordered phase-separated membranes is now reasonably well understood, but little is known about this phase preferences of multi-pass membrane proteins. Here, it is shown that the disease-linked tetraspan integral membrane protein, PMP22, displays a pronounced preference to partition into the ordered phase, a preference that is reversed by disease mutations. This phase preference may be related to the role of PMP22 in cholesterol homeostasis in myelinating Schwann cells, a role that is also known to be disrupted under conditions of CMTD peripheral neuropathy caused by pmp22 mutations.

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A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice

Cited by 33 publications

References 71 publications

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

Peripheral Myelin Protein 22 Preferentially Partitions into Ordered Phase Membrane Domains

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