shawnferguson.bsky.social

The vault associates with membranes in situ The eukaryotic vault particle is a giant ribonucleoprotein complex that assembles into an iconic barrel-like cage. Its cellular function has remained elusive despite extensive characterization. Using ...

Vaults. They are cell biology's greatest puzzle! This preprint from Martin Beck's lab shows them docked on ER membranes with a ribosome inside. What on earth is going on there??

#CellBiology #WTFology

www.biorxiv.org/content/10.6...

Congratulations to Amanda Bentley-DeSousa of the Ferguson lab for her paper being selected as one of JCB’s most impactful papers of 2025! @shawnferguson.bsky.social

We have a great lineup of invited speakers, with many additional speaking slots to be filled from submitted abstracts.
If you have exciting new work or a desire to swim here, please apply early.

I am excited to be co-organizing the 2026 Gordon Research Conference on Lysosomes & Endocytosis continuing a community tradition that has now spanned more than 50 years.
www.grc.org/lysosomes-an...

LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses Increased activity of leucine-rich repeat kinase 2 (LRRK2) is an important risk factor for Parkinson’s disease. LRRK2 localizes to lysosomal membranes, and changes in lysosome physiology are emerging ...

New research led by Devin Clegg that defines how lysosome swelling and lysosome deacidification evoke distinct routes for LRRK2 activation: doi.org/10.1101/2025...

Bentley-DeSousa, Roczniak-Ferguson and @shawnferguson.bsky.social reveal converging roles of STING and #lysosome damage in activating LRRK2 at #lysosomes via interactions between LRRK2 & GABARAP rupress.org/jcb/article/...

📕 From The Year In Cell Biology: rupress.org/jcb/collecti...
#CellBio2025

JIP4 KO proximal tubular lysosomes are mislocalized towards the basolateral membrane and contain storage material.

CRN Team De Camilli reveals a new molecular mechanism that regulates cystine efflux from lysosomes. This work is relevant to #Parkinsons research, as recent studies show JIP4 is downstream of LRRK2.

🔗 Read their #preprint: bit.ly/4l8zCkf

✏️ @shawnferguson.bsky.social @laylanassar.bsky.social

From Parkinson’s Foundation Research Center to Powerhouse: How Yale Became a Leader in Parkinson’s Science

📖Read the latest Advancing Research blog about the impact the @parkinsondotorg.bsky.social 2019 Research Center Award had on PD research at Yale University.
@schandralab.bsky.social
@shawnferguson.bsky.social
@pdc-lab.bsky.social
@yaleneuro.bsky.social

www.parkinson.org/blog/researc...

Connecticut cactus flower season 🌵

Carbide Wilson ruins.
Gatineau Park, Quebec

Exploring Waterville Valley, NH

We are also interested in links to Parkinson’s disease based on recent studies that place JIP4 downstream of LRRK2 gain-of-function mutations, a major genetic cause of autosomal-dominant inherited Parkinson's disease. JIP4-mediated cystine release may therefore be relevant for Parkinson's disease.

With this new knowledge, we wonder if cysteamine, a therapy for cystinosis, would also help people with recently discovered loss of function mutations in JIP4?

Just like in cystinosis, proximal tubule lysosomes are particularly sensitive to loss of JIP4! They lose their apical enrichment and exhibit a major storage defect!

We demonstrate, in both cultured human cells and a new JIP4 knockout mouse model, that loss of JIP4 phenocopies key features of cystinosis, the well-characterized lysosome storage disease caused by CTNS loss-of-function mutations.

Layla also we define the basis for a new lysosome storage disease arising from JIP4 loss-of-function mutations as well as a new category of lysosome storage disease arising from disruption of the machinery that regulates degradation of a nutrient transporter.

Our work from cultured human cells and a newly developed knockout mouse model demonstrates that the JIP4 scaffold protein suppresses ubiquitin-mediated degradation of cystinosin (CTNS), the transporter responsible for cystine efflux from lysosomes.

JIP4 deficiency causes a novel lysosome storage disease arising from impaired cystine efflux 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

I am excited to share our new preprint! Led by @laylanassar.bsky.social , we have found a new JIP4-dependent mechanism that controls the efflux of cystine from lysosomes. Our findings have implications for both lysosome biology and human disease: doi.org/10.1101/2025...

Multiple recent studies, including 3 impressive natural experiments, consistently show a link between Shingles vaccines and reduced dementia. This week a nationwide S Korea study added a reduction of cardiovascular events
My summary Table. More here on dementia erictopol.substack.com/p/the-shingl...

Pink lady slipper orchid

Lipid-degrading small molecule kills cancer cells by ferroptosis A molecule designed to activate iron locked up in organelles called lysosomes and thereby induce cell death might offer a way to tackle treatment-resistant cancer.

Fantastic new study from Raphael Rodriguez' lab shows that induced proximity concepts can be used to induce Ferroptosis! Inducing proximity of lysosomal iron and lipids induces lipid peroxidation! What a cool concept! Have a look at our News/Views with @olzmannlab.bsky.social shorturl.at/cbc8D

Progranulin accumulates in the Golgi of microglia in the motor cortex of LRP10 KO mice

This research was supported by @pfresearchteam.bsky.social , @asapresearch.parkinsonsroadmap.org and The Bluefield Project to Cure FTD.

These discoveries are a foundation for future investigations of how this newly defined relationship between progranulin (GRN) and LRP10 affects the neurodegenerative diseases linked to these genes that include frontotemporal dementia, Parkinson’s disease, Lewy body dementia and Alzheimer’s disease.

LRP10 promotes trafficking of progranulin and prosaposin to lysosomes Mutations in LRP10, a low-density lipoprotein receptor family member, cause familial Parkinson's disease and dementia with Lewy bodies. However, its direct cellular functions remain largely undefined....

Here’s a new set of discoveries led by Francesca Filippini: doi.org/10.1101/2025...
We found that LRP10 promotes the efficient delivery of progranulin to lysosomes and that microglia are particularly sensitive to loss of LRP10.

LRP10 promotes trafficking of progranulin and prosaposin to lysosomes https://www.biorxiv.org/content/10.1101/2025.05.02.651888v1

The bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage - Nature Cell Biology 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.

☕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.
bit.ly/4jT01lz

Antibodies don't work.

NLRP3 is by far the most studied inflammasome — yet <30% of commercial antibodies were specific.

Only 4 of 14 tested antibodies detected NLRP3 specifically.

Antibodies must be validated before use.

Full report by @ycharos.bsky.social : zenodo.org/records/1162...