Subventricular zone lipidomic architecture loss in Huntington's disease

Hunter, Mandana; Demarais, Nicholas J.; Faull, Richard L.M.; Grey, Angus C.; Curtis, Maurice A.

doi:10.1111/jnc.14468

Cited by 36 publications

(31 citation statements)

References 95 publications

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“…160 CAG repeats [231]. The altered sphingolipid metabolism has also been noted in a variety of other cellular and animal HD models [226], although the changes seem to be less clearly weighted towards cell death than in, e.g., AD [228]. However, the reduced S1P levels observed in R6/2 mice [226] appear to be a relevant potential therapeutic target, as FTY720 has been demonstrated to improve neuronal activity, reduce brain atrophy, improve motor function, and increase R6/2 animal survival [232].…”

Section: Sphingolipids In Huntington’s Disease and Amyotrophic Lateramentioning

confidence: 99%

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

et al. 2019

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Bioactive sphingolipids—ceramide, sphingosine, and their respective 1-phosphates (C1P and S1P)—are signaling molecules serving as intracellular second messengers. Moreover, S1P acts through G protein-coupled receptors in the plasma membrane. Accumulating evidence points to sphingolipids' engagement in brain aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis. Metabolic alterations observed in the course of neurodegeneration favor ceramide-dependent pro-apoptotic signaling, while the levels of the neuroprotective S1P are reduced. These trends are observed early in the diseases’ development, suggesting causal relationship. Mechanistic evidence has shown links between altered ceramide/S1P rheostat and the production, secretion, and aggregation of amyloid β/α-synuclein as well as signaling pathways of critical importance for the pathomechanism of protein conformation diseases. Sphingolipids influence multiple aspects of Akt/protein kinase B signaling, a pathway that regulates metabolism, stress response, and Bcl-2 family proteins. The cross-talk between sphingolipids and transcription factors including NF-κB, FOXOs, and AP-1 may be also important for immune regulation and cell survival/death. Sphingolipids regulate exosomes and other secretion mechanisms that can contribute to either the spread of neurotoxic proteins between brain cells, or their clearance. Recent discoveries also suggest the importance of intracellular and exosomal pools of small regulatory RNAs in the creation of disturbed signaling environment in the diseased brain. The identified interactions of bioactive sphingolipids urge for their evaluation as potential therapeutic targets. Moreover, the early disturbances in sphingolipid metabolism may deliver easily accessible biomarkers of neurodegenerative disorders.

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Section: Sphingolipids In Huntington’s Disease and Amyotrophic Lateramentioning

confidence: 99%

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

et al. 2019

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“…Finally, an altered glycolipid metabolism was also detected in the AD brain samples [151]. Furthermore, MALDI imaging was used to elucidate alterations in the lipid architecture of brains from patients with Huntington disease [152].…”

Section: Which Matrix Fits Which Lipid Class?mentioning

confidence: 99%

Recent Developments of Useful MALDI Matrices for the Mass Spectrometric Characterization of Lipids

et al. 2018

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Matrix-assisted laser desorption/ionization (MALDI) is one of the most successful “soft” ionization methods in the field of mass spectrometry and enables the analysis of a broad range of molecules, including lipids. Although the details of the ionization process are still unknown, the importance of the matrix is commonly accepted. Both, the development of and the search for useful matrices was, and still is, an empirical process, since properties like vacuum stability, high absorption at the laser wavelength, etc. have to be fulfilled by a compound to become a useful matrix. This review provides a survey of successfully used MALDI matrices for the lipid analyses of complex biological samples. The advantages and drawbacks of the established organic matrix molecules (cinnamic or benzoic acid derivatives), liquid crystalline matrices, and mixtures of common matrices will be discussed. Furthermore, we will deal with nanocrystalline matrices, which are most suitable to analyze small molecules, such as free fatty acids. It will be shown that the analysis of mixtures and the quantitative analysis of small molecules can be easily performed if the matrix is carefully selected. Finally, some basic principles of how useful matrix compounds can be “designed” de novo will be introduced.

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“…Mounting evidence points to different roles for C1P in the nervous system. A 5-fold increase in C1P levels in the subventricular zone in Huntington disease patients has been reported, with no associated changes in Cer levels; this increase might represent a response to the chronic brain damage in these patients and might either reflect an attempt at neuroprotection and enhanced neurogenesis or contribute to neuroinflammation and neurodegeneration (Hunter et al, 2018). C1P has neuroprotective effects in the nervous system.…”

Section: Searching For Ceramide-1-phosphate Functions In the Retinamentioning

confidence: 99%

Sphingolipids as Emerging Mediators in Retina Degeneration

Simón

Spalm

Vera

et al. 2019

Front. Cell. Neurosci.

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The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph), and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression. This review analyzes the functions of these sphingolipids in retina cell types and their possible pathological roles. Cer appears as a key arbitrator in diverse retinal pathologies; it promotes inflammation in endothelial and retina pigment epithelium (RPE) cells and its increase is a common feature in photoreceptor death in vitro and in animal models of retina degeneration; noteworthy, inhibiting Cer synthesis preserves photoreceptor viability and functionality. In turn, S1P acts as a double edge sword in the retina. It is essential for retina development, promoting the survival of photoreceptors and ganglion cells and regulating proliferation and differentiation of photoreceptor progenitors. However, S1P has also deleterious effects, stimulating migration of Müller glial cells, angiogenesis and fibrosis, contributing to the inflammatory scenario of proliferative retinopathies and age related macular degeneration (AMD). C1P, as S1P, promotes photoreceptor survival and differentiation. Collectively, the expanding role for these sphingolipids in the regulation of critical processes in retina cell types and in their dysregulation in retina degenerations makes them attractive targets for treating these diseases.

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Subventricular zone lipidomic architecture loss in Huntington's disease

Cited by 36 publications

References 95 publications

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

Recent Developments of Useful MALDI Matrices for the Mass Spectrometric Characterization of Lipids

Sphingolipids as Emerging Mediators in Retina Degeneration

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