Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

Biomedicines, Год журнала: 2023, Номер 11(10), С. 2793 - 2793

Опубликована: Окт. 14, 2023

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), well a seemingly distinct Niemann-Pick type C with primarily juvenile onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets, microglia, peripheral macrophages, regulatory T cells (Tregs); the complement system; other soluble factors. In this review, we compare these diseases from clinical point of view highlight common pathways mechanisms protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies overlapping dysfunctions diseases. These approaches but not limited immunisation, cascade blockade, microbiome regulation, inhibition signal transduction, Treg boosting, stem transplantation.

Язык: Английский

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An overview of the role of Niemann-pick C1 (NPC1) in viral infections and inhibition of viral infections through NPC1 inhibitor

Cell Communication and Signaling, Год журнала: 2023, Номер 21(1)

Опубликована: Дек. 14, 2023

Abstract Viruses communicate with their hosts through interactions proteins, lipids, and carbohydrate moieties on the plasma membrane (PM), often resulting in viral absorption via receptor-mediated endocytosis. Many viruses cannot multiply unless host’s cholesterol level remains steady. The large endo/lysosomal protein (MP) Niemann-Pick C1 (NPC1), which is involved cellular transport, a crucial intracellular receptor for infection. NPC1 ubiquitous housekeeping essential controlled efflux from lysosomes. Its human absence results type C disease, deadly lysosomal storage disorder. an host component filovirus entrance, infection, pathogenesis. For NPC1’s function unnecessary. Furthermore, blocking limits entry replication of African swine fever virus by disrupting homeostasis. Cell entrance quasi-enveloped variants hepatitis A E has also been linked to NPC1. By controlling levels, necessary effective release reovirus cores into cytoplasm. Drugs that limit activity are against several viruses, including SARS-CoV Type I Feline Coronavirus (F-CoV). These findings reveal as potential therapeutic target treating illnesses demonstrate its significance infections. This article provides synopsis infections review inhibitors may be used counteract Graphical

Язык: Английский

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Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

Опубликована: Сен. 13, 2023

Many of the potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), but also a seemingly distinct Niemann-Pick type C with primarily juvenile-onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets microglia, peripheral macrophages, or regulatory T cells (Tregs), complement system, other soluble factors. In this review, we will compare these from clinical point view out common pathways mechanisms protein aggregation, neurodegeneration and/or neuroinflammation that could potentially lead to shared treatment strategies. We describe approaches treating dysfunctions disorders, moving immunization microbiome regulation stem treatment.

Язык: Английский

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The multiple facets of Rab proteins modulating the cellular distribution of cholesterol from the late endosomal compartment

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Год журнала: 2025, Номер 1872(3), С. 119896 - 119896

Опубликована: Янв. 7, 2025

Язык: Английский

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Bromodomain Proteins as New Drug Target for an Inborn Lysosomal Defect

Опубликована: Янв. 1, 2025

Inborn errors of lysosomal function often provoke disorders presenting highly variable onset, diverse visceral, neurologic and psychiatric symptoms reduced life spans. A prime example is Niemann-Pick type C disease (NPCD). At present, therapeutic options are limited to palliative care disease-modifying drugs, there a need for new treatments. Here, we explored bromodomain extra-terminal domain (BET) proteins as drug target NPCD using patient-derived skin fibroblasts. Treatment cells with JQ1, prototype BET protein inhibitor, enhanced the level NPC1 protein, diminished expansion cholesterol accumulation, induced extracellular release components in dose- time-dependent manner. The effect JQ1 on levels was largely independent from patient line tested, but extent reduction varied line-dependent Lastly, accumulation by inhibition activity histone deacetylases, respectively. Taken together, our results provide further evidence epigenetic regulation cellular homeostasis. Pharmacologic should be candidate approach tool understand basic mechanisms lipid metabolism.

Язык: Английский

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Detecting the Difficult: An Intronic NPC1 Variant Hiding in Plain Sight

American Journal of Medical Genetics Part A, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

ABSTRACT An illustration of the importance manual data review for identifying rare intronic variants adjacent to homopolymers is presented here. A 14‐year‐old male with Niemann‐Pick Type C disease confirmed biochemically was only found have a heterozygous pathogenic variant by molecular analysis. Next Generation Sequencing (NGS) identified c.709C>T; p.Pro237Ser variant, which likely not reported initially because it consistently classified as benign or benign. association c.709C>T second NPC1 (c.1947 + 5G>C) leading use cryptic splice donor site has been before. Further evaluation Sanger sequencing detected c.1947 5G>C causative in this patient. Detection allelic change autosomal recessive inborn errors metabolism and other genetic disorders vital establishing diagnosis, initiating new therapies, testing at risk family members. The case here illustrates that may be readily current short‐read NGS technologies due downstream should evaluated regularly, especially presence another variant.

Язык: Английский

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Perspective Chapter: Next-Generation Sequencing and Variant Cataloging for Screening and Diagnosis of Sphingolipidoses and Mucopolysaccharidoses

IntechOpen eBooks, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

This chapter provides a comprehensive examination of how next-generation sequencing (NGS) technologies are transforming prenatal and neonatal care, particularly in the diagnosis lysosomal diseases (LDs). These rare, inherited conditions caused by defects metabolism. If not detected treated early, they can lead to significant disabilities reduced life expectancy. The specifically focuses on use NGS diagnose screen sphingolipidoses (SLDs) mucopolysaccharidoses (MPSs). It covers molecular pathogenesis, classification, main symptomatology diseases. reviews progress made identifying genes associated with SLDs MPSs cataloging clinically relevant genetic variants. Additionally, it highlights growing adoption for screening institutions such as academic research centers, private healthcare providers, government health agencies. also discusses challenges implementation, regulation, outlines future directions its application medicine.

Язык: Английский

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Sterol O-Acyltransferase 1 (SOAT1): A Genetic Modifier of Niemann-Pick Disease, Type C1

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4217 - 4217

Опубликована: Апрель 11, 2024

Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment. Marked heterogeneity has been observed in individuals with same NPC1 genotype, thus suggesting significant effect modifier genes. Prior work demonstrated that decreased SOAT1 activity severity an mouse model. Thus, we hypothesized polymorphism associated expression might influence phenotype. Phenotyping and genomic sequencing 117 was performed as part Natural History trial. included determination burden. Significant clinical present homozygous for NPC1I1061T variant siblings. Analysis polymorphism, rs1044925 (A>C), showed association C-allele earlier age neurological onset. The may be higher Annualized Severity Index Score well increased frequency liver seizures. A appears genetic This finding consistent prior data showing phenotypic Npc1-/-:Soat1-/- mice supports efforts investigate potential inhibitors therapy NPC1.

Язык: Английский

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Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

Язык: Английский

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Clinical, genotypic, and neuropsychological profile in a series of patients with Niemann-Pick type C disease

Frontiers in Neurology, Год журнала: 2025, Номер 16

Опубликована: Фев. 26, 2025

Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder with wide spectrum of clinical manifestations and genetic variability. This cross-sectional study aimed to comprehensively describe the neuropsychological impact NPC investigate its correlation specific genotypes. Eight patients from six unrelated families were included in this study. Their age at symptom onset ranged between 2 16 years, all presenting ataxia, dysarthria, cognitive impairment. Following initiation miglustat treatment, five showed decrease Scale for Assessment Rating Ataxia (SARA) score, whereas three demonstrated subsequent increases. Five underwent brain magnetic resonance imaging scans, revealing white matter abnormalities and/or volumetric reduction cases. Despite small sample size, overall performance cohort was significantly below average. The Family Environment highlighted positive structural patterns, particularly regarding Personal Growth System Maintenance. Genetic analysis identified mutations NPC1 gene that correlated severity impairments outcomes. indicated consistent association behavioral impairments, correlating variants. Notably, one subgroup higher prevalence psychotic symptoms, suggesting potential link

Язык: Английский

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