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Cathepsin C-Catalyzed Ligation Generates Intralysosomal Amyloid Fibrils from Dipeptide Esters
Ruben D Elias1, Robert T O'Neill1, Idil I Demiralp1
1Department of Chemistry, The Scripps Research Institute; La Jolla, CA, USA.
Biorxiv : the Preprint Server for Biology
|January 7, 2026
Summary
Scientists created amyloid fibrils inside lysosomes using dipeptides, revealing a new mechanism for neurodegenerative disease research. This discovery offers tools to study lysosomal dysfunction and develop potential therapies.
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Endolysosomal dysfunction is linked to neurodegenerative diseases.
- Amyloid fibrils are a hallmark of many neurodegenerative conditions.
Purpose of the Study:
- To investigate the rapid generation of intralysosomal amyloid fibrils.
- To explore the role of Cathepsin C in amyloid formation and its implications for neurodegeneration.
Main Methods:
- Cell treatment with dipeptide methyl esters.
- Cryo-electron tomography for structural analysis.
- Assessment of lysosomal membrane permeabilization and ESCRT-repair response.
Main Results:
- Dipeptide treatment rapidly generated intralysosomal amyloid fibrils.
- Cathepsin C mediated sequence-dependent oligopeptide self-assembly into fibrils.
- Fibril growth, not deposition, caused lysosomal membrane permeabilization.
- Oligopeptide fibrils cross-seeded Tau(P301S) aggregation at lysosomal sites.
- Dipeptide sequence variation modulated lysosomal membrane permeabilization and repair.
Conclusions:
- A novel method for generating intralysosomal amyloid fibrils was established.
- This approach provides new tools for studying lysosomal biology and neurodegenerative disease mechanisms.
- The findings highlight the potential of targeting Cathepsin C-dependent pathways.
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