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

Pathmasiri, Koralege C; Pergande, Melissa R; Tobias, Fernando; Rebiai, Rima; Rosenhouse‐Dantsker, Avia; Bongarzone, Ernesto R.; Cologna, Stephanie M.

doi:10.1194/jlr.ra119000606

Cited by 10 publications

(7 citation statements)

References 58 publications

(57 reference statements)

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“…Specifically, a recent study using 2D MALDI-MSI indicated decreases in PIP and PIP 2 in the cerebellum of the NPC1-null mice, providing evidence for the alteration of PI downstream metabolites in the NPC1 disease. 40 Besides, some other reports observed changes in protein kinase C and phosphatidylinositol-3 kinase expression in the NPC1 animals. 41,42 Our findings of increases of PI and LPI combined with decreases of its downstream metabolites in previous reports indicated that some kinases in the phosphoinositide synthesis pathway might be impaired.…”

Section: ■ Results and Discussionmentioning

confidence: 95%

Three-Dimensional Imaging of Whole-Body Zebrafish Revealed Lipid Disorders Associated with Niemann–Pick Disease Type C1

et al. 2021

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Imaging of lipids of whole-body specimens in two-dimensional (2D) analysis provides a global picture of the lipid changes in lipid-disturbed diseases, enabling a better understanding of lipid functions and lipid-modulation processes in different organs. However, 2D imaging of a single cross section can hardly characterize the whole-body lipid alterations. In this work, a three-dimensional matrix-assisted laser desorption/ionization mass spectrometry imaging (3D MALDI-MSI) approach was developed for analysis of whole-body zebrafish, for the first time, and applied to identify altered lipids and map their spatial distributions by using a zebrafish model of Niemann–Pick disease type C1 (NPC1), a neurovisceral lipid storage disorder causing both neurodegenerative disorder and visceral organ damage. The constructed 3D fish model provided comprehensive information on the 3D distribution of lipids of interest and allowed direct correlations between these lipids and organs of the fish. Obtained results revealed that several sphingolipids and phospholipids showed significant alterations and exhibited different localization patterns in various organs such as the brain, spinal cord, intestines, and liver–spleen region in the npc1 gene mutant fish compared to those of the wild type. The whole-body 3D MALDI-MSI approach revealed unique lipid signatures for different NPC1-affected organs, which might offer insights into the link between the impaired lipid storage and subsequent clinical symptoms, such as neurodegeneration and hepatosplenomegaly.

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Section: ■ Results and Discussionmentioning

confidence: 95%

Three-Dimensional Imaging of Whole-Body Zebrafish Revealed Lipid Disorders Associated with Niemann–Pick Disease Type C1

et al. 2021

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“…Phosphorylation of K V 2.1 by CDK5 enhances channel clustering 67 . Furthermore, CDK5 kinase activity is elevated in NPC disease 68 , 90 . We find that CDK5 activators, p35/p39 have increased expression in NPC disease and inhibition of CDK5 kinase activity with roscovitine abrogates enhancement of both K V 2.1 and Ca V 1.2 clustering in the PM of NPC neurons.…”

Section: Discussionmentioning

confidence: 99%

NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease

et al. 2023

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Lysosomes communicate through cholesterol transfer at endoplasmic reticulum (ER) contact sites. At these sites, the Niemann Pick C1 cholesterol transporter (NPC1) facilitates the removal of cholesterol from lysosomes, which is then transferred to the ER for distribution to other cell membranes. Mutations in NPC1 result in cholesterol buildup within lysosomes, leading to Niemann-Pick Type C (NPC) disease, a progressive and fatal neurodegenerative disorder. The molecular mechanisms connecting NPC1 loss to NPC-associated neuropathology remain unknown. Here we show both in vitro and in an animal model of NPC disease that the loss of NPC1 function alters the distribution and activity of voltage-gated calcium channels (CaV). Underlying alterations in calcium channel localization and function are KV2.1 channels whose interactions drive calcium channel clustering to enhance calcium entry and fuel neurotoxic elevations in mitochondrial calcium. Targeted disruption of KV2–CaV interactions rescues aberrant CaV1.2 clustering, elevated mitochondrial calcium, and neurotoxicity in vitro. Our findings provide evidence that NPC is a nanostructural ion channel clustering disease, characterized by altered distribution and activity of ion channels at membrane contacts, which contribute to neurodegeneration.

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“…PtdIns-4,5-P 2 plays crucial roles in neurons, including vesicle docking at the plasma membrane during endocytosis at the synapse, coupling exo- and endocytosis and regulating actin assembly . Phosphoinositides, in particular PtdIns-4,5-P 2 , are significantly depleted in the NPC1-disease neurons, leading to hyperexcitability. , It has also been recently reported than NPC1 regulated the distribution of phosphatidylinositol-4 kinases at lysosome and Golgi membranes . Although the expression level of Synj1 in NPC1 I1061T fibroblasts is reportedly not significantly changed, the implication of Synj1 in hyperexcitability through modification of PtdIns-4,5-P 2 cannot yet be ruled out …”

Section: Resultsmentioning

confidence: 96%

Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

Javanshad,

Nguyen,

Azaria

et al. 2024

J. Proteome Res.

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NPC intracellular cholesterol transporter 1 (NPC1) is a multipass, transmembrane glycoprotein mostly recognized for its key role in facilitating cholesterol efflux. Mutations in the NPC1 gene result in Niemann-Pick disease, type C (NPC), a fatal, lysosomal storage disease. Due to the progressively expanding implications of NPC1-related disorders, we investigated endogenous NPC1 protein−protein interactions in the mouse cortex and human-derived iPSCs neuronal models of the disease through coimmunoprecipitation-coupled with LC-MS based proteomics. The current study investigated protein−protein interactions specific to the wild-type and the most prevalent NPC1 mutation (NPC1 I1061T ) while filtering out any protein interactor identified in the Npc1 −/− mouse model. Additionally, the results were matched across the two species to map the parallel interactome of wild-type and mutant NPC1 I1061T . Most of the identified wild-type NPC1 interactors were related to cytoskeleton organization, synaptic vesicle activity, and translation. We found many putative NPC1 interactors not previously reported, including two SCAR/WAVE complex proteins that regulate ARP 2/3 complex actin nucleation and multiple membrane proteins important for neuronal activity at synapse. Moreover, we identified proteins important in trafficking specific to wild-type and mutant NPC1 I1061T . Together, the findings are essential for a comprehensive understanding of NPC1 biological functions in addition to its classical role in sterol efflux.

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

Cited by 10 publications

References 58 publications

Three-Dimensional Imaging of Whole-Body Zebrafish Revealed Lipid Disorders Associated with Niemann–Pick Disease Type C1

Three-Dimensional Imaging of Whole-Body Zebrafish Revealed Lipid Disorders Associated with Niemann–Pick Disease Type C1

NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease

Endogenous Protein–Protein Interaction Network of the NPC Cholesterol Transporter 1 in the Cerebral Cortex

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