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Related Concept Videos

Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

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Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
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Lysosomal Hydrolases01:22

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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Lysosomes01:31

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Lysosomes are membrane-enclosed spherical sacs derived from the Golgi apparatus. The most important function of the lysosome is degrading macromolecules and biological polymers that are released during membrane trafficking events such as the secretory, endocytic, autophagic, and phagocytic pathways. The degradation is carried out by several hydrolytic enzymes active in an acidic environment of the lysosomal lumen. These acid hydrolases are involved in cellular processes such as cell signaling,...
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ER Retrieval Pathway01:45

ER Retrieval Pathway

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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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Related Experiment Video

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Targeted Plasma Membrane Delivery of a Hydrophobic Cargo Encapsulated in a Liquid Crystal Nanoparticle Carrier
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Lysosomal Targeting of β-Cyclodextrin.

Andrea Mascherpa1, Nozomii Ishii1, Ayelen Tayagui1

  • 1School of Physical and Chemical Sciences, University of Canterbury, Private Bag 4800, Christchurch, 8140, New Zealand.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|October 20, 2022
PubMed
Summary

Attaching mannose-6-phosphate (M6P) glycans to beta-cyclodextrin (β-CD) enhances its cellular uptake and transport to lysosomes. This glycan conjugation may improve β-CD

Keywords:
carbohydratescyclodextrinsfluorescent probeslysosomemannose-6-phosphate

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Drug Delivery

Background:

  • Beta-cyclodextrins (β-CDs) are approved therapeutics used in over 30 clinical settings.
  • β-CDs show therapeutic potential for lysosomal storage disorders by binding and extracting accumulated hydrophobic metabolites.
  • Lysosomal targeting of enzymes typically involves N-glycans with mannose-6-phosphate (M6P) residues.

Purpose of the Study:

  • To investigate if conjugating M6P-terminated N-glycans to β-CD enhances its cellular uptake and lysosomal transport.
  • To evaluate the therapeutic potential of M6P-glycan modified β-CD for lysosomal storage disorders.

Main Methods:

  • Covalent attachment of a synthetic biantennary bis-M6P-terminated N-glycan to β-CD.
  • Formation of a host-guest complex with a Cy5 fluorophore for visualization.
  • Study of cellular internalization and lysosomal transport in a mammalian cell line using fluorescence microscopy.

Main Results:

  • Attachment of M6P-glycans significantly increased the rate of β-CD cellular internalization.
  • M6P-glycan conjugation also enhanced the rate of β-CD transport to the lysosome.
  • Fluorescence microscopy confirmed improved cellular uptake and lysosomal trafficking of the modified β-CD.

Conclusions:

  • M6P-glycan conjugation is a viable strategy to enhance β-CD cellular uptake and lysosomal delivery.
  • This approach may improve the therapeutic efficacy of β-CD for treating diseases involving lysosomal metabolite accumulation.
  • Targeted delivery via M6P-glycans represents a promising advancement in β-CD-based therapeutics.