Upregulation of SNAP25 by HDAC inhibition ameliorates NPC disease phenotypes via autophagy induction

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE185644 | GEO | 2024/09/26

REPOSITORIES: GEO