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

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.

Download Full-text

Gastrointestinal Tract Pathology in a BALB/c Niemann–Pick Disease Type C1 Null Mouse Model

Digestive Diseases and Sciences ◽

10.1007/s10620-018-4914-x ◽

2018 ◽

Vol 63 (4) ◽

pp. 870-880 ◽

Cited By ~ 4

Author(s):

Antony Cougnoux ◽

Miyad Movassaghi ◽

Jaqueline A. Picache ◽

James R. Iben ◽

Fatemeh Navid ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Mouse Model ◽

Disease Type ◽

Null Mouse ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Pick Disease

Download Full-text

Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.757482 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lien Van Hoecke ◽

Caroline Van Cauwenberghe ◽

Kristina Dominko ◽

Griet Van Imschoot ◽

Elien Van Wonterghem ◽

...

Keyword(s):

Choroid Plexus ◽

Premature Death ◽

Loss Of Function ◽

Lipid Storage Disease ◽

Niemann Pick Disease ◽

Progressive Neurodegeneration ◽

Type C ◽

Niemann Pick

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

Download Full-text

Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20246288 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6288 ◽

Cited By ~ 1

Author(s):

Michael Rabenstein ◽

Nico Murr ◽

Andreas Hermann ◽

Arndt Rolfs ◽

Moritz J. Frech

Keyword(s):

Synaptic Transmission ◽

Purkinje Cells ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Western Blot Testing ◽

Progressive Neurodegeneration ◽

Niemann Pick ◽

Cerebellar Purkinje Cells ◽

Deficient Mice ◽

Gabaergic Synaptic Transmission

Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1−/− mice. In addition, Purkinje cells of NPC1−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1.

Download Full-text

Faculty Opinions recommendation of High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727681051.793542524 ◽

2018 ◽

Author(s):

Barbara Borroni

Keyword(s):

Massively Parallel Sequencing ◽

Late Onset ◽

Disease Type ◽

Massively Parallel ◽

Data Sets ◽

Sequencing Data ◽

Niemann Pick Disease ◽

High Incidence ◽

Niemann Pick ◽

Pick Disease

Download Full-text

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets

Genetics in Medicine ◽

10.1038/gim.2015.25 ◽

2015 ◽

Vol 18 (1) ◽

pp. 41-48 ◽

Cited By ~ 107

Author(s):

Christopher A. Wassif ◽

Joanna L. Cross ◽

James Iben ◽

Luis Sanchez-Pulido ◽

Antony Cougnoux ◽

...

Keyword(s):

Massively Parallel Sequencing ◽

Late Onset ◽

Disease Type ◽

Massively Parallel ◽

Data Sets ◽

Sequencing Data ◽

Niemann Pick Disease ◽

High Incidence ◽

Niemann Pick ◽

Pick Disease

Download Full-text

Main Olfactory and Vomeronasal Epithelium Are Differently Affected in Niemann-Pick Disease Type C1

International Journal of Molecular Sciences ◽

10.3390/ijms19113563 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3563 ◽

Cited By ~ 1

Author(s):

Martin Witt ◽

René Thiemer ◽

Anja Meyer ◽

Oliver Schmitt ◽

Andreas Wree

Keyword(s):

Cathepsin D ◽

Disease Type ◽

Cell Renewal ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Dividing Cells ◽

Progressive Neurodegeneration ◽

Receptor Neurons ◽

Niemann Pick ◽

Pick Disease

Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Methods: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPβCD), or a monotherapy with HPβCD alone. Results: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% ± 12% in Npc1−/− mice, and 270% ± 10% in combination- treated Npc1−/− animals. The monotherapy with HPβCD led to an increase of 261% ± 10.5% compared to sham-treated Npc1−/− mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1−/− mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1−/− mice displays an increased neuroregenerative potential, indicating compensatory cell renewal.

Download Full-text