Study shows that psilocybin acts on nerves to prevent the painful condition called peripheral neuropathy.

Liao and Bussi discuss work from Marco et al., which identifies an endocytic mechanism for internalization of therapeutic ASOs.

Liao and Bussi discuss work from Marco et al., which identifies an endocytic mechanism for internalization of therapeutic ASOs.

This Roadmap clarifies terminology, core physics, biological roles, and key theoretical, computational, and experimental challenges to guide a coordinated effort toward a predictive understanding and ...

E. coli releases vesicles that repair membrane damage and promote survival under antibiotic stress.

Utrecht University

The Institute for Digital Molecular Analytics and Science (IDMxS), officially launched on 1 December 2022, is a Research Centre of Excellence (RCE) supported by a total investment of around S$160 mill...

Tan and colleagues develop DNA nanodevices to detect the pH of the lysosomal outer surface, observing an acidic layer generated by TMEM175 that regulates lysosome positioning in response to changes in...

Amyloid fibril-associated endolysosomal dysfunction is implicated in multiple neurodegenerative diseases. We report the rapid generation of intralysosomal amyloid fibrils by simply treating cells with certain dipeptide methyl esters. Cathepsin C mediates the ligation of dipeptides into oligopeptides that, sequence-dependently, self-assemble into amyloid fibrils. Progressive fibril growth, not fibril deposition, mediates lysosomal membrane permeabilization. Cryo-electron tomography studies reveal intralysosomal fibrils and broken lysosomal membranes upon dipeptide treatment. Certain oligopeptide fibril structures are competent to cross-seed the aggregation of neurodegeneration-associated Tau(P301S) at lysosomal sites. Similarly, the degree of lysosomal membrane permeabilization and ESCRT-repair response can be tuned with dipeptide sequence variation. The presented Cathepsin C-dependent amyloid fibril formation approach lends itself toward the development of novel tools to further probe lysosomal biology and pathobiology. ### Competing Interest Statement The authors have declared no competing interest. National Institute on Aging, https://ror.org/049v75w11, RF1AG073418 National Center for Advancing Translational Sciences, https://ror.org/04pw6fb54 Department of Education, USA, P031S240270 Freedom Together Foundation Chan Zuckerberg Initiative (United States), CZII-2023–327779 George E. Hewitt Foundation for Medical Research

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. In vitro 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. ### Competing Interest Statement J.W.H. is a co-founder of Caraway Therapeutics, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (Caraway) and is a scientific advisory board member for Lyterian Therapeutics. Aligning Science Across Parkinson's, https://ror.org/03zj4c476, ASAP-000350, ASAP-000282, ASAP-024268 Boehringer Ingelheim Fonds, https://ror.org/00dkye506 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, GRK 2566/1 Pew Scholars Program NIH Common Fund, https://ror.org/001d55x84, RF1NS125674, R01NS110395 Fred and Joan Goldberg Post-doctoral Fellowship European Research Council, 101041982

Biopolymers can couple to membrane lipids and condense to prewet membranes. Here a range of membrane perturbations in reconstituted systems and cells show that the prewetting is sensitive to membrane ...

After damage from pathogenic, chemical or physical stress, endolysosomal membranes are repaired and resealed by the endosomal sorting complex required for transport (ESCRT) machinery, but how this mem...

Although organellar compartmentalization is primarily established by the delimiting phospholipid bilayer membranes, the contribution of proteins has been less appreciated. Recently, studies across man...

The secretion mechanism of the Parkinson’s disease risk factor GPNMB highlights lysosomal dysfunction as a disease mechanism.

In this Review, Li and Underhill discuss recent advances in understanding the process of phagocytosis. The authors highlight how phagocytosis is integral for innate immune sensing and explain how the ...

The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways sig...

Lee et al. use an aggregation-prone CLN4 mutant that causes lysosomal damage in neurons and show that in non-neurons, the ubiquitin ligase CHIP prevents CLN4-dependent lysotoxicity via microautophagy.

Join us at the Keystone Symposia on Membrane Dynamics, Repair and Disease, February 2026, in Keystone, with field leaders!

Join us at the Keystone Symposia on Membrane Dynamics, Repair and Disease, February 2026, in Keystone, with field leaders!

ZF5.3 is a mini-protein that escapes endosomes efficiently. Work to understand the underlying mechanism now reveals that ZF5.3 unfolds at pH values lower than 5.5 through protonation of Zn(II)-bound H...

The Tweety homologue TTYH2 is identified as the lipid transfer mediator for APOE-containing lipoproteins.

The cellular response to lysosomal damage involves fine-tuned mechanisms of membrane repair, lysosome regeneration and lysophagy, but how these different processes are coordinated is unclear. Here we ...

Lysosomes break down macromolecules, clear cellular waste and recycle nutrients such as cystine. We describe a novel mechanism whereby JIP4 regulates lysosomal cystine storage by controlling the abundance of cystinosin (CTNS), the transporter responsible for lysosomal cystine efflux. To this end, JIP4, previously characterized as a motor adaptor and kinase signaling scaffold, suppresses TMEM55B-dependent ubiquitylation of CTNS. Loss of JIP4 reduces CTNS protein levels, leading to lysosomal cystine accumulation and lysosomal storage defects that phenocopy loss of CTNS in both human cells and the renal proximal tubules of JIP4 knockout mice. These phenotypes mirror cystinosis, the lysosomal storage disease caused by CTNS loss-of-function. Our findings thus reveal a fundamental process that controls the efflux of lysosomal cystine and has relevance to understanding human disease arising from JIP4 mutations. ### Competing Interest Statement The authors have declared no competing interest. NIH, AG085824, AG062210, R35GM150619 Michael J. Fox Foundation, https://ror.org/03arq3225, ASAP-000580

A study presents EndoMAP.v1, a resource that combines information on protein interactions and crosslink-supported structural predictions to map the interaction landscape of early endosomes.

Intrinsically disordered regions (IDRs) in proteins play essential roles in cellular function. A growing body of work has shown that IDRs often interact with partners in a manner that does not depend ...

Some cancer cells exhibit high loads of reactive iron in lysosomes, and this feature is exploited by using fentomycin-1, a newly developed small molecule, to induce ferroptosis.

Lysosomal phospholipase PLA2G15 was identified as a physiological BMP hydrolase whose activity depends on unique esterification and stereochemistry of BMP and offers a potential therapeutic targe...

After transplantation into the brain of patients with Parkinson’s disease, allogeneic dopaminergic progenitors derived from induced pluripotent stem cells survived, produced dopamine and did not form ...

Wang et al. show the recruitment of the lipid channel protein VPS13C and formation of VPS13C-dependent contacts between endoplasmic reticulum and lysosomes after lysosomal damage.

Autophagy has long been presumed to decline with age, underpinning its designation as a hallmark of ageing. However, emerging evidence challenges this notion, showing tissue-specific variability and, ...

This study uncovers Rab GTPases as evolutionarily conserved signals mediating selective autophagy, targeting damaged mitochondria, lipid droplets, and path

Tambrin et al. show that the Cdc42/Rac GAP ARHGAP12 promotes the flux of macromolecules across tight junctions by suppressing junctional actin assembly and tension via N-WASP and the Arp2/3 complex. T...

High spatiotemporal precision tracking using 3D MINFLUX shows that nuclear import and export occur in overlapping regions of the central pore, providing insight into transport across the nuclear pore ...

Mammalian cells present RNA-binding proteins on the cell surface that form clustered domains containing glycoRNAs.