Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C

Colaço, Alexandria; Fernández-Suárez, María E.; Shepherd, Dawn; Gal, Lihi; Bibi, Chen; Chuartzman, Silvia; Diot, Alan; Morten, Karl; Eden, Emily R.; Porter, Forbes D.; Poulton, Joanna; Platt, Nick; Schuldiner, Maya; Platt, Frances M.

doi:10.26508/lsa.201800253

Cited by 12 publications

(10 citation statements)

References 73 publications

(76 reference statements)

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“…It is pertinent that NPC1 protein can mediate the intracellular transport of copper 55 and belongs to the resistance-nodulation-cell division (RND) permease superfamily that in prokaryotes function as proton symporters in the coupled efflux of multiple substrates including metals 56 . Intriguingly, genetic screens to identify protein binding partners of Nrc1, the yeast orthologue of NPC1 protein, identified the iron transporter Fth1 that is responsible for the movement of intravacuolar iron stores 57,58 .…”

Section: Discussionmentioning

confidence: 99%

Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Chen

Siebel²,

Colaço³

et al. 2022

Wellcome Open Res

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Background: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal storage disorder characterized by the accumulation of multiple lipids in the late endosome/lysosomal system and reduced acidic store calcium. The lysosomal system regulates key aspects of iron homeostasis, which prompted us to investigate whether there are hematological abnormalities and iron metabolism defects in NPC1. Methods: Iron-related hematological parameters, systemic and tissue metal ion and relevant hormonal and proteins levels, expression of specific pro-inflammatory mediators and erythrophagocytosis were evaluated in an authentic mouse model and in a large cohort of NPC patients. Results: Significant changes in mean corpuscular volume and corpuscular hemoglobin were detected in Npc1-/- mice from an early age. Hematocrit, red cell distribution width and hemoglobin changes were observed in late-stage disease animals. Systemic iron deficiency, increased circulating hepcidin, decreased ferritin and abnormal pro-inflammatory cytokine levels were also found. Furthermore, there is evidence of defective erythrophagocytosis in Npc1-/- mice and in an in vitro NPC1 cellular model. Comparable hematological changes, including low normal serum iron and transferrin saturation and low cerebrospinal fluid ferritin were confirmed in NPC1 patients. Conclusions: These data suggest loss of iron homeostasis and hematological abnormalities in NPC1 may contribute to the pathophysiology of this disease.

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Section: Discussionmentioning

confidence: 99%

Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Chen

Siebel²,

Colaço³

et al. 2022

Wellcome Open Res

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“…Taken together, these ndings suggest that CYP46A1 defects and resultant metabolite dyshomeostasis contribute to NP-C disorder, possibly through autophagic dysfunction, and they can serve as promising therapeutic targets for cerebellar ataxia. Notably, it has been reported that Ca 2+ , eCB, and other signaling pathways also contribute to NP-C pathogenesis [373][374][375]. These may be downstream or side effects of cytochrome P450 de ciency, which require further veri cation.…”

Section: Niemann-pick Type C Protein 1 (Npc1)mentioning

confidence: 98%

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

Zhao

Zhang

Fan

et al. 2021

Preprint

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Cerebellar ataxia is a neurological disorder originating in the cerebellum and can be divided into different subtypes. The etiology of these disorders is complicated, especially in inherited disorders. Currently, nearly all disorders remain incurable. To precisely diagnose and treat these diseases, studies on their molecular mechanisms have been conducted extensively in the past. Accumulating evidence has demonstrated that some common pathogenic mechanisms exist within each subtype of inherited ataxia. However, no reports have indicated whether there is a common mechanism among the different subtypes of cerebellar ataxia. In this review, we summarize the available references and databases on neurological disorders characterized by cerebellar ataxia and show that a subset of genes involved in lipid homeostasis form a new group that may cause ataxic disorders through a common mechanism. This common signaling pathway can provide a valuable reference for future diagnosis and treatment of ataxic disorders.

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“…However, yeast cells bear a homologue of NPC2, which can replace the human version [108]. Moreover, yeast cells have been used to screen for pathways influencing the outcome of NPC1 deficiency [109][110][111] and to explore the molecular mechanism of sterol transfer based on structural data [25]. The knock-down of NPC1 and NPC2 homologues in the sterol auxotroph pathogen Entamoeba histolytica revealed their contribution to cholesterol uptake (Ehnpc1, Ehnpc2) [112].…”

Section: Non-mammalian Modelsmentioning

confidence: 99%

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

Pallottini

Pfrieger

2020

IJMS

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Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.

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Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C

Cited by 12 publications

References 73 publications

Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

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