Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model

Han, Shiqian; Ren, Meng; Kuang, Tianyin; Pang, Mao; Guan, Dongwei; Liu, Yesong; Wang, Yong; Zhang, Wengeng; Ye, Zhijia

doi:10.1007/s12035-021-02526-3

Cited by 5 publications

(7 citation statements)

References 52 publications

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“…Most of these pathways with exception of small molecule biochemistry, vitamin metabolism and protein folding and refolding were found to be affected in npc1 Δ56/ Δ56 larvae. RNAseq analysis in NPC brain organoids showed that most of the gene differences were those related to nervous system development (Lee et al, 2020) RNAseq performed in cerebellum and astrocytes of an NPC mouse model (Cougnoux et al, 2021;Han et al, 2021) revealed most discrepancies with npc1 zebrafish model with altered pathways like immune system process, plasma membrane, protein binding, glutamate transporter, glycosphingolipid biosynthesis, TGF-beta signaling, protein digestion and absorption, cell adhesion molecule, and neuroactive ligand-receptor interaction pathways. Only immune system process, plasma membrane and cell adhesion pathways were altered in npc1 Δ56/ Δ56 larvae.…”

Section: Discussionmentioning

confidence: 99%

Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation

Regaldie¹,

Fieiras²,

Villamayor³

et al. 2023

Preprint

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Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. NPC1 is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences. We generated a zebrafish NPC1 model by CRISPR/Cas9 carrying a homozygous mutation in exon 22, which encodes the end of the cysteine-rich luminal loop of the protein. This is the first zebrafish model with a mutation in this gene region, which is frequently involved in the human disease. We observed a high lethality in npc1 mutants, with all larvae dying before reaching the adult stage. Npc1 mutant larvae were smaller than wild type (wt) and their motor function was impaired. We observed vacuolar aggregations positive to cholesterol and sphingomyelin staining in the liver, intestine, renal tubules and cerebral gray matter of mutant larvae. RNAseq comparison between npc1 mutants and controls showed 249 differentially expressed genes, including genes with functions in neurodevelopment, lipid exchange and metabolism, muscle contraction, cytoskeleton, angiogenesis, and hematopoiesis. Lipidomic analysis revealed significant reduction of cholesteryl esters and increase of sphingomyelin in the mutants. Compared to previously available zebrafish models, our model seems to recapitulate better the early onset forms of the NPC disease. Thus, this new model of NPC will allow future research in the cellular and molecular causes/consequences of the disease and on the search for new treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation

Regaldie¹,

Fieiras²,

Villamayor³

et al. 2023

Preprint

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“…These disorders are extremely rare and for most of them the implication of lncRNAs is yet to be investigated. Indeed, no evidence is currently available linking lncRNAs with Batten disease and metachromatic leukodystrophy, but indications are emerging connecting these molecules to SMA and NPD [68,69].…”

Section: Lncrnas In Pediatric Neurodegenerative Diseasesmentioning

confidence: 99%

“…Symptoms can range from hepatosplenomegaly (enlarged liver and spleen) to neurological manifestations such as developmental regression, loss of motor skills, and intellectual decline [67]. Again, evidence linking lncRNAs to NPD disease is limited, but RNA-sequencing could be helpful towards this goal and one recent study was performed in the cerebellum of a murine model of NPD [69]. This study highlighted 272 dysregulated lncRNAs in NPD, and amongst them, lncRNA H19 was selected for further characterization [69].…”

Section: Lncrnas In Pediatric Neurodegenerative Diseasesmentioning

confidence: 99%

Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications

Pandini,

Rey,

Cereda

et al. 2023

Pharmaceuticals

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Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and when a pathological condition is present. We describe the role of lncRNAs in neural development, highlighting their significance in processes such as neural stem cell proliferation, differentiation, and synaptogenesis. Dysregulation of specific lncRNAs is associated with multiple pediatric neurological diseases, such as neurodevelopmental or neurodegenerative disorders and brain tumors. The collected evidence indicates that there is a need for further research to uncover the full spectrum of lncRNA involvement in pediatric neurological diseases and brain tumors. While challenges exist, ongoing advancements in technology and our understanding of lncRNA biology offer hope for future breakthroughs in the field of pediatric neurology, leveraging lncRNAs as potential therapeutic targets and biomarkers.

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“…RNAseq performed in cerebellum and astrocytes of an NPC mouse model (Cougnoux et al, 2021;Han et al, 2021) revealed most discrepancies with npc1 zebrafish model with altered pathways like immune system process, plasma membrane, protein binding, glutamate transporter, glycosphingolipid biosynthesis, TGF-beta signaling, protein digestion and absorption, cell adhesion molecule, and neuroactive ligand-receptor interaction pathways. Only immune system process, plasma membrane and cell adhesion pathways were altered in npc1 Δ56/ Δ56 larvae.…”

mentioning

confidence: 91%

Severe neurometabolic phenotype in npc1−/− zebrafish with a C-terminal mutation

Quelle-Regaldie

Gandoy-Fieiras²,

Rodríguez-Villamayor³

et al. 2023

Front. Mol. Neurosci.

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Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. NPC1 is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences. We generated a zebrafish NPC1 model by CRISPR/Cas9 carrying a homozygous mutation in exon 22, which encodes the end of the cysteine-rich luminal loop of the protein. This is the first zebrafish model with a mutation in this gene region, which is frequently involved in the human disease. We observed a high lethality in npc1 mutants, with all larvae dying before reaching the adult stage. Npc1 mutant larvae were smaller than wild type (wt) and their motor function was impaired. We observed vacuolar aggregations positive to cholesterol and sphingomyelin staining in the liver, intestine, renal tubules and cerebral gray matter of mutant larvae. RNAseq comparison between npc1 mutants and controls showed 284 differentially expressed genes, including genes with functions in neurodevelopment, lipid exchange and metabolism, muscle contraction, cytoskeleton, angiogenesis, and hematopoiesis. Lipidomic analysis revealed significant reduction of cholesteryl esters and increase of sphingomyelin in the mutants. Compared to previously available zebrafish models, our model seems to recapitulate better the early onset forms of the NPC disease. Thus, this new model of NPC will allow future research in the cellular and molecular causes/consequences of the disease and on the search for new treatments.

show abstract

Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model

Cited by 5 publications

References 52 publications

Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation

Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation

Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications

Severe neurometabolic phenotype in npc1−/− zebrafish with a C-terminal mutation

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Cerebellar Long Noncoding RNA Expression Profile in a Niemann-Pick C Disease Mouse Model

Cited by 5 publications

References 52 publications

Severe neurometabolic phenotype innpc1-/-zebrafish with a C-terminal mutation

Severe neurometabolic phenotype innpc1-/-zebrafish with a C-terminal mutation

Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications

Severe neurometabolic phenotype in npc1−/− zebrafish with a C-terminal mutation

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Product

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Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation

Severe neurometabolic phenotype innpc1^-/-zebrafish with a C-terminal mutation