Mass spectrometry imaging reveals ganglioside and ceramide localization patterns during cerebellar degeneration in the Npc1−/− mouse model

Tobias, Fernando; Pathmasiri, Koralege C; Cologna, Stephanie M.

doi:10.1007/s00216-019-01989-7

Cited by 34 publications

(29 citation statements)

References 68 publications

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“…Accurate mass measurement matching and MS/MS fragmentation with database searching identified m/z 1382.8 as GM2(d36:1) and 1410.8 as GM2(d38:1). This is consistent with previous reports of ganglioside increases in NPC1 (21,33). On tissue MS/MS spectra are provided in supplemental Figs.…”

Section: Maldi-msi Reveals Altered Phosphoinositides In Npc1supporting

confidence: 92%

“…In another study, a point mutation NPC1 mouse model was used to develop a combined infrared microscopy-MSI approach, but lipid mapping was not extensively performed (20). More recently, we have shown that ceramides exhibit patterned alterations in the cerebellum of Npc1 / mice via MSI (21). Herein, we show that PIP 2 and PIP are decreased in cerebellar tissue from the NPC1 mouse model as early as 3 weeks of age, whereas a decrease in PI is observed at a later stage of the disease progression by LC/MS.…”

Section: Decreased Cerebellar Phosphoinositides In Npc1mentioning

confidence: 99%

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Mass spectrometry imaging and LC/MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice

Pathmasiri

Pergande

Tobias

et al. 2020

Journal of Lipid Research

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Niemann-Pick disease type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized a consensus spectra analysis of MS imaging data sets and orthogonal LC/MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including PI, PIP, and PIP2, in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-kinase type 2α in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model, as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.

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Section: Maldi-msi Reveals Altered Phosphoinositides In Npc1supporting

confidence: 92%

Section: Decreased Cerebellar Phosphoinositides In Npc1mentioning

confidence: 99%

Mass spectrometry imaging and LC/MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice

Pathmasiri

Pergande

Tobias

et al. 2020

Journal of Lipid Research

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“…Notably, multiple ceramides that are increased are observed to incorporate an C18:1 fatty acyl chain. Ceramides have been reported to be increased in NPC1 and may be linked to known apoptosis …”

Section: Resultsmentioning

confidence: 99%

Lipidomic Analysis Reveals Altered Fatty Acid Metabolism in the Liver of the Symptomatic Niemann–Pick, Type C1 Mouse Model

et al. 2019

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Niemann–Pick disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As a result of the genetic defect, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system causing both visceral and neurological defects. These manifest clinically as hepatosplenomegaly, liver dysfunction, and neurodegeneration. While significant progress has been made to better understand NPC1, the downstream effects of cholesterol storage and the major mechanisms that drive these pathologies remains less understood. In this study, it is sought to investigate free fatty acid levels in Npc1−/− mice with focus on the polyunsaturated ω‐3 and ω‐6 fatty acids. Since fatty acids are the main constituents of numerous lipids species, a discovery based lipidomic study of liver tissue in Npc1−/− mice is also performed. To this end, alterations in fatty acid synthesis, including the ω‐3 and 6 fatty acids, are reported. Further, alterations in enzymes that regulate the synthesis of ω‐3 and 6 fatty acids are reported. Analysis of the liver lipidome reveals alterations in both storage and membrane lipids including ceramides, fatty acids, phosphatidylcholamines, phosphatidylglycerols, phosphatidylethanolamines, sphingomyelins, and triacylglycerols in Npc1−/− mice at a late stage of disease.

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“…Secondary storage is thought to have a substantial role in the pathophysiology of LSDs. This idea is supported by the finding that secondary substrates localize in the brain areas that are most affected by the disease pathology (Tobias et al , 2019; Viana, et al , 2020) and that depletion of secondary substrates in experimental conditions (e.g., GM3 in the Niemann‐Pick type C1 mouse model) results in amelioration of neuropathology and disease manifestations (Lee et al , 2014). Secondary storage may also impair vesicle trafficking.…”

Section: Introductionmentioning

confidence: 92%

The rapidly evolving view of lysosomal storage diseases

2021

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Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic‐lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high‐throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.

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Mass spectrometry imaging reveals ganglioside and ceramide localization patterns during cerebellar degeneration in the Npc1−/− mouse model

Cited by 34 publications

References 68 publications

Mass spectrometry imaging and LC/MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice

Mass spectrometry imaging and LC/MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice

Lipidomic Analysis Reveals Altered Fatty Acid Metabolism in the Liver of the Symptomatic Niemann–Pick, Type C1 Mouse Model

The rapidly evolving view of lysosomal storage diseases

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