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

ABSTRACT: 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.

SUBMITTER: Van Hoecke L

PROVIDER: S-EPMC8555471 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Van Hoecke Lien L Van Cauwenberghe Caroline C Dominko Kristina K Van Imschoot Griet G Van Wonterghem Elien E Castelein Jonas J Xie Junhua J Claeys Wouter W Vandendriessche Charysse C Kremer Anna A Borghgraef Peter P De Rycke Riet R Hecimovic Silva S Vandenbroucke Roosmarijn E RE

Frontiers in cellular neuroscience 20211015

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 <i>Npc1</i> or <i>Npc2</i> 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 ...[more]

PMID: 34720883

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Project description:ObjectivesThe aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood.DesignFifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients.ResultsOver half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function.ConclusionsThis is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Dataset Information

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

Publications

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

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