Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes

Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. <i>In vitro</i> reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-01-19
DOI
https://doi.org/10.64898/2026.01.17.700056
Primary Topic
Lysosomal Storage Disorders Research
Type
article
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article

Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes

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bioRxiv (Cold Spring Harbor Laboratory)
Lysosomal Storage Disorders Research
article

Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes

Sonja Welsch, Javier Lizarrondo, Dietmar Hammerschmid, Danielle Ann Grotjahn, D. Li, Michaela Medina, Maike Windbergs, Di Wu, Felix Kraus, Andre Schwarz, Jeremy Pflaum, Erin M. Schuman, Jan F. M. Stuke, Wenxin Zhang, Johann Brenner, Jonas Brill, Julia H Grass, Florian Wilfling, Lena-Marie Soltow, Julian Langer, Wade J. Harper, Natalie Weber, Simon Ohlerich
article en

Abstract

Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. <i>In vitro</i> reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.

bioRxiv (Cold Spring Harbor Laboratory)
Goethe University Frankfurt (DE), Scripps Research Institute (US), Max Planck Institute of Biophysics (DE), Max Planck Institute for Brain Research (DE), Max Planck Institute of Biochemistry (DE), Research Network (United States) (US), Harvard Stem Cell Institute (US)
Openalex Percentile: Top 84%
Lysosomal Storage Disorders Research
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