Upregulation of SNAP25 by HDAC inhibition ameliorates NPC disease phenotypes via autophagy induction
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ABSTRACT:
PROVIDER: PRJNA770263 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16290048.fastq.gz | Fastqsanger.gz | |||
| SRR16290049.fastq.gz | Fastqsanger.gz | |||
| SRR16290050.fastq.gz | Fastqsanger.gz | |||
| SRR16290051.fastq.gz | Fastqsanger.gz |
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Project description:Niemann-Pick Type C disease (NPC) is a rare fatal neurodegenerative disorder caused by mutations in NPC1 and NPC2 gene leading to abnormal accumulation of unesterified cholesterol in lysosomes. There have been no available treatments and FDA approved drugs for treating NPC. SAHA, a HDAC inhibitor (HDACi), was shown to ameliorate NPC disease phenotypes and considered as a therapeutics candidate but its mechanism of action is not fully clarified yet. Here, we investigated whether SAHA and HNHA, a new derivative of SAHA, reduced cholesterol level and then performed NGS analysis for these two compounds in NPC-iNSCs. Intracellular trafficking, secretion, and vesicular transport factors were highly enriched by two compounds treatment in NPC-iNSCs. Notably, SNAP25, a subunit of SNARE complex was significantly upregulated. Since autophagic flux is impaired in NPC cells due to SNARE complex deficiency, we hypothesized that increasing SNAP25 could contribute to form autolysosomes. When SNAP25 was overexpressed in NPC cells, it compensated deficient Vamp8-SNAP29-STX17 complexes to Vamp8-SNAP25-STX17 complexes then it restores autolysosomes leading to reduce accumulated LC3, LAMP1a, and p62. Consistently, SNAP25 was upregulated by HDAC inhibitors treatment and recovered deficient autophagic flux in vitro, and in vivo. Therefore, upregulation of SNAP25 by HDAC inhibition ameliorated NPC phenotypic and behavioral disorder in 2D culture system and NPC-/- mouse model. These results demonstrated a key role of SNAP25 to ameliorate NPC disease phenotypes and provided HDAC inhibitors as new therapeutic candidates for NPC treatment
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Project description:Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2(300Q) transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2(300Q) transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment. Analysis of striatum, cortex, and cerebellum from R6/2(300Q) transgenic mice before and after treatment with the HDAC inhibitor 4b
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Project description:Analysis of differential expression between NPC and non-NPC tissues at miRNA expression level. We used a miRNA microarray platform to investigate the profile between NPC tissues and normal nasopharyngeal tissues to evaluate the relationship between miRNA expression and NPC. Recognition of the aberrant miRNAs and enrichment pathway analysis of predicted target gene may provide some clues to estimate the mechanism of miRNA effects on NPC carcinogenesis mediated by miRNA-mRNA regulation. Total RNA was extracted from 8 NPC tissues compared to 4 nasopharyngeal tissues. We peformed the Illumina miRNA microarray to identify the differentially expressed miRNA between NPC tissues and normal nasopharyngeal tissues.
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