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  • Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK.

Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK.

Autophagy (2017-06-15)
Sheng Dai, Andrés E Dulcey, Xin Hu, Christopher A Wassif, Forbes D Porter, Christopher P Austin, Daniel S Ory, Juan Marugan, Wei Zheng
ABSTRACT

The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing cholesterol accumulation in NPC cells is uncertain and its molecular target is unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog of HPβCD, restored impaired macroautophagy/autophagy flux in Niemann-Pick disease, type C1 (NPC1) cells. This effect was mediated by a direct activation of AMP-activated protein kinase (AMPK), an upstream kinase in the autophagy pathway, through MβCD binding to its β-subunits. Knockdown of PRKAB1 or PRKAB2 (encoding the AMPK β1 or β2 subunit) expression and an AMPK inhibitor abolished MβCD-mediated reduction of cholesterol storage in NPC1 cells. The results demonstrate that AMPK is the molecular target of MβCD and its activation enhances autophagy flux, thereby mitigating cholesterol accumulation in NPC1 cells. The results identify AMPK as an attractive target for drug development to treat NPC.

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Sigma-Aldrich
Sodium palmitate, ≥98.5%
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Sigma-Aldrich
Anti-phospho ULK1 Antibody (Ser777), from rabbit, purified by affinity chromatography
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SKUPack SizeAvailabilityPrice
0.2 mL
1 Available to ship on January 06, 2025
Details...
A recombinant, preservative-free antibody is available for your target. Try ZRB1312
¥98,300
100 μL
1 Available to ship on January 06, 2025
Details...
A recombinant, preservative-free antibody is available for your target. Try ZRB1312
¥98,300
0.5 mL
1 Available to ship on January 06, 2025
Details...
A recombinant, preservative-free antibody is available for your target. Try ZRB1312
¥195,000

To order products, please contact your local dealer.