MS-based Proteomics Analysis of Cerebrospinal Fluid from Niemann-Pick type C Disease Patients
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ABSTRACT:
INSTRUMENT(S): timsTOF Pro 2
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Forbes D. Porter
PROVIDER: MSV000093519 | MassIVE | Tue Nov 28 08:13:00 GMT 2023
REPOSITORIES: MassIVE
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Project description:Niemann-Pick, type C1 (NPC1) is a fatal, neurodegenerative disease, which belongs to the family of lysosomal diseases. In NPC1, endo/lysosomal accumulation of unesterified cholesterol and sphingolipids arise from improper intracellular trafficking resulting in multi-organ dysfunction. With the proximity between the brain and cerebrospinal fluid (CSF), performing differential proteomics provides a means to shed light to changes occurring in the brain. In this study, CSF samples obtained from NPC1 individuals and unaffected controls were used for protein biomarker identification. A subset of these individuals with NPC1 are being treated with miglustat, a glycosphingolipid synthesis inhibitor. Of the 300 identified proteins, 71 proteins were altered in individuals with NPC1 compared to controls including cathepsin D, and members of the complement family. Included are a report of 10 potential markers for monitoring therapeutic treatment. We observed that pro-neuropeptide Y (NPY) was significantly increased in NPC1 individuals relative to healthy controls; however, individuals treated with miglustat displayed levels comparable to healthy controls. In further investigation, NPY levels in a NPC1 mouse model corroborated our findings. We posit that NPY could be a potential therapeutic target for NPC1 due to its multiple roles in the central nervous system such as attenuating neuroinflammation and reducing excitotoxicity.
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Project description:Recent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 protein. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid, which is known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.
2020-12-21 | GSE157676 | GEO
Project description:Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials.
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Project description:Here we perform RNAsequencing on isolated microglia from wild-type and NP-C mice throughout disease course. We sequence microglia from WT and NPC mice at 1, 3, 6, and 9 weeks old. We also treat mice with the CSF1R inhibitor PLX5622 and sequence remaining microglia from treated and control mice.
2023-06-09 | GSE152158 | GEO
Project description:Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (p < 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (rs = -0.42, FDR adj. p < 0.0001) and increased with increased Annual Severity Increment Score (rs = 0.52, FDR adj. p < 0.0001). Baseline CSF total Tau levels were decreased 40% (p = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p < 0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p = 0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.
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Project description:Analysis of microRNA (miRNA) expression in CSF from prodromal Huntington disease patients.
2020-05-10 | GSE150174 | GEO
Project description:BackgroundNiemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype is heterogeneous with variable age of onset, classical NPC1 is a pediatric disorder. Currently there are no therapies approved by the FDA and therapeutics trials for NPC1 are complicated by disease rarity, heterogeneity, and the relatively slow rate of neurological decline. Thus, identification of disease relevant biomarkers is necessary to provide tools that can support drug development efforts for this devastating neurological disease.MethodsProximal extension assays (O-link® Explore 1536) were used to compare cerebrospinal fluid (CSF) samples from individuals with NPC1 enrolled in a natural history study and non-NPC1 comparison samples. Relative expression levels of 1467 proteins were determined, and candidate protein biomarkers were identified by evaluating fold-change and adjusted Kruskal-Wallis test p-values. Selected proteins were orthogonally confirmed using ELISA. To gain insight into disease progression and severity we evaluated the altered protein expression with respect to clinically relevant phenotypic aspects: NPC Neurological Severity Score (NPC1 NSS), Annual Severity Increment Score (ASIS) and age of neurological onset.ResultsThis study identified multiple proteins with altered levels in CSF from individuals with NPC1 compared to non-NPC1 samples. These included proteins previously shown to be elevated in NPC1 (NEFL, MAPT, CHIT1, CALB1) and additional proteins confirmed by orthogonal assays (PARK7, CALB2/calretinin, CHI3L1/YKL-40, MIF, CCL18 and ENO2). Correlations with clinically relevant phenotypic parameters demonstrated moderate negative (p = 0.0210, r = -0.41) and possible moderate positive (p = 0.0631, r = 0.33) correlation of CSF CALB2 levels with age of neurological onset and ASIS, respectively. CSF CHI3L1 levels showed a moderate positive (p = 0.0183, r = 0.40) correlation with the concurrent NPC1 NSS. A strong negative correlation (p = 0.0016, r = -0.648) was observed between CSF CCL18 and age of neurological onset for childhood/adolescent cases. CSF CCL18 levels also showed a strong positive correlation (p = 0.0017, r = 0.61) with ASIS.ConclusionOur study identified and validated multiple proteins in CSF from individuals with NPC1 that are candidates for further investigation in a larger cohort. These analytes may prove to be useful as supportive data in therapeutic trials.Trial registrationsNCT00344331, NCT00001721, NCT02931682.
| S-EPMC9887810 | biostudies-literature
Project description:BackgroundNiemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive disorder due to pathological variants of NPC1. The NPC1 phenotype is characterized by progressive cerebellar ataxia and cognitive impairment. Although classically a childhood/adolescent disease, NPC1 is heterogeneous with respect to the age of onset of neurological signs and symptoms. While miglustat has shown to be clinically effective, there are currently no FDA approved drugs to treat NPC1. Identification and characterization of biomarkers may provide tools to facilitate therapeutic trials. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a protein which is highly expressed by neurons and is a biomarker of neuronal damage. We thus measured cerebrospinal fluid (CSF) levels of UCHL1 in individuals with NPC1.MethodsCSF levels of UCHL1 were measured using a Quanterix Neuroplex 4 assay in 94 individuals with NPC1 and 35 age-appropriate comparison samples. Cross-sectional and longitudinal CSF UCHL1 levels were then evaluated for correlation with phenotypic measures and treatment status.ResultsCSF UCHL1 levels were markedly elevated (3.3-fold) in individuals with NPC1 relative to comparison samples. The CSF UCHL1 levels showed statistically significant (adj p < 0.0001), moderate, positive correlations with both the 17- and 5-domain NPC Neurological Severity Scores and the Annual Severity Increment Scores. Miglustat treatment significantly decreased (adj p < 0.0001) CSF UCHL1 levels by 30% (95% CI 17-40%).ConclusionsCSF UCHL1 levels are elevated in NPC1, increase with increasing clinical severity and decrease in response to therapy with miglustat. Based on these data, UCHL1 may be a useful biomarker to monitor disease progression and therapeutic response in individuals with NPC1.
| S-EPMC10803635 | biostudies-literature
Project description:Increasing evidence implicates lysosomal dysfunction in the pathogenesis of neurodegenerative diseases, including the rare inherited lysosomal storage disorders (LSDs) and the most common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease (AD and PD). The goal of this work was to analyze whether there are changes in the lysosomal glycocalyx in a cellular model of a LSD Niemann-Pick type C disease (NPC). Using the ferrofluid nanoparticles we isolated lysosomal organelles from NPC1-null and CHOwt cells. Mass spectrometry identification of lysosomal proteins was performed in order to determine the enrichment efficiency for N-glycome profiling of the lysosomal glycocalyx in NPC disease cellular model.
2018-03-21 | PXD008438 | Pride
Project description:OBJECTIVE:Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures. METHODS:Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival. RESULTS:Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2-8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1-5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia - a potent risk factor for aspiration pneumonia and premature death in NP-C - demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function. CONCLUSIONS:The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.
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